血清晚期糖基化终末产物和可溶性晚期糖基化终末产物受体与阿尔茨海默病及血管性痴呆关系的研究

目的探讨血清中晚期糖基化终末产物(AGEs)、可溶性晚期糖基化终末产物受体(sRAGE)的水平与阿尔茨海默病(AD)、血管性痴呆(Va D)的关系。方法收集兰州大学第二医院神经内科2017年2月到2018年1月收治的149例患者,根据MMSE量表及相应的纳入排除标准,将患者进行分组,其中AD组34例,脑梗死后痴呆(Va D)组64例,脑梗死非痴呆(N-Va D)组51例,选择同期在性别、年龄、文化程度上无差异、无严重疾病的住院体检者31例作为正常对照组。比较4组间的一般资料及简易智能精神状态检查量表(MMSE)评分,比较血清AGEs、sRAGE在不同组别之间的差异,并分析其与AD和Va D的关系。结果 AD组和N-Va D组的AGEs水平高于Va D组和正常对照组,差异有统计学意义(P 0. 05)。Va D组和正常对照组之间,AD组和N-Va D组之间的AGEs水平比较,差异无统计学意义(P 0. 05)。ROC曲线分析显示血清AGEs对AD有较低诊断价值。Spearman秩相关法分析显示,年龄(r=-0. 168,P 0. 05)与MMSE评分呈负相关;体重指数(r=0. 151,P 0. 05)与MMSE评分呈正相关。4组在性别、年龄、糖尿病方面不存在显著性差异(P 0. 05)。4组间sRAGE水平比较无显著性差异(P 0. 05)。结论血清AGEs可能与AD的发生、发展有关; AGEs对AD有较低的诊断价值。     

Advanced glycation end products co-localized with astrocytes and microglial cells in Alzheimer’s disease brain

   In the previous study [Takeda et al. (1996) Neurosci Lett 221: 17–21], we reported that the advanced glycation end products (AGEs) in the external space of neuronal perikarya (extraneuroperikaryal AGE deposits) were significantly abundant in the Alzheimer’s brain. In this study, we investigated the spatial relationship of the extraneuroperikaryal AGE (carbocymethyllysine and pentosidine) deposits in astrocytes and microglial cells in the Alzheimer’s disease brain using double immunolabelling for AGEs and astrocyte or microglial cell markers. Most of the extraneuroperikaryal AGE deposits were co-localized with glial fibrillary acidic protein-positive astrocytes. AGE deposit-bearing astrocytes also contained Gomori-positive granules. Furthermore, some of the extraneuroperikaryal AGE deposits were co-localized with microglial cells. These extraneuroperikaryal AGEs may activate astrocyte and microglia, and play a role in pathogenesis of Alzheimer’s disease. Received: 8 September 1997 / Revised: 19 November 1997 / Accepted: 12 February 1998     

晚期糖基化终末产物及其受体与脑梗死的关系

脑梗死又称缺血性脑卒中.在我国,每年死于脑血管病的人数近150万,患病的近1300万,全国每年新增病例大约200万,其中脑梗死患者占624%之多[1].有香港学者报道,中国的脑梗死发病率明显高于西方发达国家[2],其是我国中老年人致残、致死的重要原因之一.脑梗死的相关研究也已引起国内外学者越来越多的关注.     

Visual feedback has differential effects on reaching movements in Parkinson’s and Alzheimer’s disease

We examine the role of visual feedback in the programming and execution of reaching movement in patients with Parkinson’s disease without cognitive impairment and patients with Alzheimer’s disease without extrapyramidal signs. Controls were normally aging subjects. All subjects moved a cursor to targets on a digitizing tablet without seeing their limb. Starting and target positions were always visible on a screen while, during movement, cursor position was either visible or blanked. They were instructed to make uncorrected movements, as fast and as accurate as possible without minimizing reaction time. In absence of visual feedback, movement accuracy in patients with AD was severely impaired. Hand paths of parkinsonian patients were as accurate as normal subjects’ with similar temporal velocity profiles and movement speed. With cursor feedback, accuracy was the same in the three groups, although movement speed and transport phase in patients with Alzheimer’s disease were significantly reduced compared to the other groups. Also, movements of parkinsonian patients showed shorter transport phase and lower mean velocity than controls’. The different characteristics of the motor performance suggests that in the two diseases visual information is used differently for both motor programming and execution: patients with Alzheimer’s disease, while scarcely using feed forward commands, relied on continuous on-line external cues. The correlation of motor performance with cognitive impairment argues against the hypothesis of basal ganglia involvement in AD. The motor abnormalities we found may represent early subclinical manifestation of apraxic disturbance. Parkinsonian patients showed higher reliance on feedback commands only with cursor feedback: this could be explained by their difficulty in engaging effectively automatic routines when distractors are present.     

Inflammation in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disorder to date. Next to its classical histopathological characteristics such as deposition of fibrillogenic amyloid β peptides and neurofibrillary tangles, an inflammatory component of the disease has been identified. This article will review which cell types contribute to this phenomenon and which pro- and anti-inflammatory mediators are being released in the AD brain. Further, it will be discussed whether there are any known pathogenetic factors that may facilitate the induction and persistence of neuroinflammatory mechanisms. While neuroinflammation has mostly been quoted as a reaction to neurodegenerative events, more recent evidence suggests that it can feedback stimulate on neurodegenerative pathomechanisms including the generation of amyloid β peptides, thereby establishing a vicious and self-perpetuating cycle. Along this line, pro- and anti-inflammatory mechanisms may also contribute to the chronicity and duration of the disease. Therefore, anti-inflammatory treatment strategies should be evaluated as possible future therapeutics for AD.     

Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer's disease

Advanced glycation end products (AGE) and the receptor for AGE (RAGE) have been implicated in the chronic complications of diabetes mellitus (DM), and have been reported to play an important role in the pathogenesis of Alzheimer's disease (AD). In this study, we established a polyclonal anti-RAGE antibody, and examined the immunohistochemical localization of amyloid beta protein (Abeta), AGE, and RAGE in neurons and astrocytes from patients with AD and DM. Our anti-RAGE antibody recognized full-length RAGE (50 kd) and N-terminal RAGE (35 kd) in human brain tissue. Abeta-, AGE-, and RAGE-positive granules were identified in the perikaryon of hippocampal neurons (especially from CA3 and CA4) in all subjects. The distribution and staining pattern of these immunopositive granules showed good concordance with each antibody. In AD, most astrocytes contained both AGE-and RAGE-positive granules and their distribution was almost the same. Abeta-positive granules were less common, but Abeta-, AGE-, and RAGE-positive granules were colocalized in one part of a single astrocyte. In DM patients and control cases, AGE-and RAGE-positive astrocytes were very rare. These finding support the hypothesis that glycated Abeta is taken up via RAGE and is degraded through the lysosomal pathway in astrocytes. In addition to the presence of AGE, the process of AGE degradation and receptor-mediated reactions may contribute to neuronal dysfunction and promote the progression of AD.     

Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease

Mateo I, Infante J, Sánchez‐Juan P, García‐Gorostiaga I, Rodríguez‐Rodríguez E, Vázquez‐Higuera JL, Berciano J, Combarros O. Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease.
Acta Neurol Scand: 2010: 121: 136–138.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – Oxidative stress is implicated in Parkinson’s disease (PD) and Alzheimer’s disease (AD), and heme oxygenase‐1 (HO‐1) is a potent antioxidant overexpressed in PD substantia nigra and AD cerebral cortex and hippocampus, indicating a possible up‐regulation of antioxidant defenses in both neurodegenerative diseases. The role of HO‐1 in peripheral blood of PD and AD patients remains unresolved. Methods – We measured serum HO‐1 levels in 107 patients with PD, 105 patients with AD, 104 controls for PD and 120 controls for AD. Results – The median serum concentration of HO‐1 was significantly higher in PD patients (2.04 ng/ml) compared with that of PD controls (1.69 ng/ml, P = 0.016), with PD patients predominating over controls in the upper tertile of serum HO‐1 levels, whereas there was more PD controls than PD patients in the lower tertile (P = 0.006). Median serum levels of HO‐1 did not differ significantly between AD patients and AD controls. Conclusion – The increase of serum HO‐1 levels in PD patients could indicate a systemic antioxidant reaction related to a chronic oxidative stress state in PD brain.     

高级糖基化终末产物在认知功能障碍发病中的作用

高级糖基化终末产物（AGEs）是由蛋白质非酶促化反应生成的不可逆的终产物,高级糖基化终末产物受体（RAGE）是其体内重要的受体。通过临床、动物实验及病理研究发现,AGEs与认知功功能损害的发生有关,对神经细胞的直接毒性作用、对β-淀粉样蛋白（Ap）、TAU蛋白及a-突触核蛋白（a—Synuclein）等修饰、炎症反应和脑血管损伤是AGEs参与认知损害发生的重要机制。通过药物拮抗AGEs的作用可能是治疗认知障碍的一个有效途径。     

Altered expression of the synuclein family mRNA in Lewy body and Alzheimer’s disease

The main objective of this study was to determine if levels of α-, β- and/or γ-synuclein mRNAs are differentially affected in brains of Lewy body disease (LBD) and Alzheimer’s disease (AD) patients, compared to controls. In control cases, highest levels of expression were observed in the neocortex and the lowest in basal ganglia and substantia nigra. β-Synuclein was the most abundant message (75–80%), followed by γ-synuclein (10–15%) and α-synuclein (8–10%). Analysis of the superior temporal cortex, a region selectively affected in LBD and AD, showed that compared to controls, levels of α-synuclein were increased in cases of diffuse LBD (DLBD), levels of β-synuclein were decreased in AD and DLBD, and levels of γ-synuclein were increased in AD cases. This study suggests that a critical balance among products of the synuclein gene is important to maintain normal brain function and that alterations in this balance might be associated with neurodegenerative disorders.     

糖基化终末产物对SH-SY5Y细胞内质网应激的影响

目的研究糖基化终末产物(AGEs)对体外培养的神经母细胞瘤细胞(SH-SY5Y)内质网应激的影响,探讨AGEs在AD发病中的可能机制。方法以糖基化修饰的牛血清白蛋白(AGE-BSA)分别处理SH-SY5Y细胞0、12、24、48 h,蛋白质免疫印迹法检测内质网应激(ERS)相关蛋白GRP78、p-eIF2α、Caspase-12的表达水平。再将细胞随机分为正常对照组(NC组)、牛血清白蛋白对照组(BSA组)、AGE-BSA组、AGE-BSA+抗RAGE中和抗体组(RAGE-Ab组)、AGE-BSA+α-硫辛酸组(ALA组)、AGE-BSA+NADPH氧化酶抑制剂DPI组(DPI组)。蛋白免疫印迹法半定量检测各组细胞ERS相关蛋白表达水平变化,同样处理后用免疫荧光染色观察GRP78、p-eIF2α表达水平,应用活性氧荧光探针DCFH-DA检测各组细胞活性氧(ROS)水平。结果 AGE-BSA处理细胞24 h后免疫蛋白印迹可见GRP78、p-eIF2α出现表达高峰,同时荧光染色可见两者高水平表达,48 h后Caspase-12表达水平显著升高,且ROS水平达到NC组的6.95倍。与AGE-BSA组相比,RAGE-Ab组、ALA组、DPI组的ROS水平都有不同程度的降低(P<0.01),同时GRP78、p-eIF2α、Caspase-12的表达水平均有明显下调(P<0.01或P<0.05)。结论 AGEs可诱导SH-SY5Y细胞ROS产生,并通过启动氧化应激及内质网应激对细胞造成损伤。     

Gesture comprehension,knowledge and production in Alzheimer’s disease

Background and purpose: Although apraxia is a typical consequence of Alzheimer’s disease (AD), the profile of apraxic impairments is still subject to debate. Here, we analysed apraxia components in patients with AD with mild‐to‐moderate or moderately severe dementia. Methods: Thirty‐one patients were included. We first evaluated simple gestures, that is, the imitation of finger and hand configurations, symbolic gestures (recognition, production on verbal command and imitation), pantomimes (recognition, production on verbal command, imitation and production with the object), general knowledge and complex gestures (tool–object association, function–tool association, production of complex actions and knowledge about action sequences). Tests for dementia (Mini Mental State Examination and the Dementia Rating Scale), language disorders, visual agnosia and executive function were also administered. Results: Compared with controls, patients showed significant difficulties (P ≤ 0.01) in subtests relating to simple gestures (except for the recognition and imitation of symbolic gestures). General knowledge about tools, objects and action sequences was less severely impaired. Performance was frequently correlated with the severity of dementia. Multiple‐case analyses revealed that (i) the frequency of apraxia depended on the definition used, (ii) ideomotor apraxia was more frequent than ideational apraxia, (iii) conceptual difficulties were slightly more frequent than production difficulties in the early stage of AD and (iv) difficulties in gesture recognition were frequent (especially for pantomimes). Conclusion: Patients with AD can clearly show gesture apraxia from the mild–moderate stage of dementia onwards. Recognition and imitation disorders are relatively frequent (especially for pantomimes). We did not find conceptual difficulties to be the main problem in early‐stage AD.     

Cyanobacterial neurotoxin BMAA in ALS and Alzheimer’s disease

Objective – The aim of this study was to screen for and quantify the neurotoxic amino acid β‐N‐methylamino‐l ‐alanine (BMAA) in a cohort of autopsy specimens taken from Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and non‐neurological controls. BMAA is produced by cyanobacteria found in a variety of freshwater, marine, and terrestrial habitats. The possibility of geographically broad human exposure to BMAA had been suggested by the discovery of BMAA in brain tissues of Chamorro patients with ALS/Parkinsonism dementia complex from Guam and more recently in AD patients from North America. These observations warranted an independent study of possible BMAA exposures outside of the Guam ecosystem. Methods – Postmortem brain specimens were taken from neuropathologically confirmed cases of 13 ALS, 12 AD, 8 HD patients, and 12 age‐matched non‐neurological controls. BMAA was quantified using a validated fluorescent HPLC method previously used to detect BMAA in patients from Guam. Tandem mass spectrometric (MS) analysis was carried out to confirm the identification of BMAA in neurological specimens. Results – We detected and quantified BMAA in neuroproteins from postmortem brain tissue of patients from the United States who died with sporadic AD and ALS but not HD. Incidental detections observed in two out of the 24 regions were analyzed from the controls. The concentrations of BMAA were below what had been reported previously in Chamarro ALS/ Parkinsonism dementia complex patients, but demonstrated a twofold range across disease and regional brain area comparisons. The presence of BMAA in these patients was confirmed by triple quadrupole liquid chromatography/mass spectrometry/mass spectrometry. Conclusions – The occurrence of BMAA in North American ALS and AD patients suggests the possibility of a gene/environment interaction, with BMAA triggering neurodegeneration in vulnerable individuals.     

AGEs对SH-SY5Y细胞增殖、凋亡以及阿尔茨海默病相关mRNA的影响

目的 研究晚期糖基化终产物(AGEs)对人神经母细胞瘤SH-SY5Y细胞株增殖、凋亡以及AD相关mRNA的影响。 方法 利用小牛血清白蛋白(BSA)和葡萄糖体外制备BSA-AGEs;将SH-SY5Y细胞与不同浓度BSA-AGEs保温后,MTT法测定SH-SY5Y细胞的增殖率,流式细胞仪测定细胞凋亡和细胞周期的变化,RT-PCR检测细胞中AD相关mRNA的表达水平。 结果 BSA-AGEs对SH-SY5Y细胞增殖有明显抑制作用,明显促进神经元的凋亡,细胞周期被阻滞于G1/G0期,呈药物浓度依赖性。RT-PCR结果表明,经过BSA-AGEs刺激后,IL-6、高迁移率族蛋白B1(HMGB1)、淀粉先质蛋白(APLP1) mRNA表达水平均明显升高。 结论 BSA-AGEs能有效抑制SH-SY5Y细胞的增殖,促进炎症细胞因子产生,诱导细胞凋亡,提示AGEs在AD的发生与发展过程中具有促进作用。     

EFNS guidelines for the diagnosis and management of Alzheimer’s disease

Background and objectives: In 2008 a task force was set up to develop a revision of the European Federation of the Neurological Societies (EFNS) guideline for the diagnosis and management of Alzheimer’s disease (AD) and other disorders associated with dementia, published in early 2007. The aim of this revised international guideline was to present a peer‐reviewed evidence‐based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with AD. Mild cognitive impairment and non‐Alzheimer dementias are not included in this guideline. Methods: The task force working group reviewed evidence from original research articles, meta‐analysis, and systematic reviews, published before May 2009. The evidence was classified and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. Results: The recommendations for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of AD, behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers were all revised as compared with the previous EFNS guideline. Conclusion: A number of new recommendations and good practice points are made, namely in CSF, neuropsychology, neuroimaging and reviewing non‐evidence based therapies. The assessment, interpretation, and treatment of symptoms, disability, needs, and caregiver stress during the course of AD require the contribution of many different professionals. These professionals should adhere to these guideline to improve the diagnosis and management of AD.     

Hippocampal estrogen β-receptor immunoreactivity is increased in Alzheimer’s disease

Post-menopausal estrogen use reduces the risk and severity of Alzheimer’s disease (AD). The present study investigates the distribution of both estrogen receptors ERα and ERβ in the human hippocampus in aged controls and in AD cases with immunohistochemistry. No ERα immunoreactivity was observed both in controls and in AD cases. On the other hand, ERβ was observed in some neuronal cells in the hippocampal subfields CA1–4, in astrocytes and in extracellular deposits both in controls and AD cases. The ERβ immunoreactivity was distinctly increased in all AD cases in cellular and extracellular localizations indicating a role for ERβ-mediated estrogen effects in AD-related neuropathology. This study provides the first demonstration of ERβ in human hippocampus in aged controls compared to AD cases.     

Estrogen receptor alpha-immunoreactive astrocytes are increased in the hippocampus in Alzheimer's disease

Postmenopausal estrogen use may decrease the risk, and delay the onset and progression, of Alzheimer's disease (AD). By means of fluorescence immunocytochemistry, the present study investigated the distribution of estrogen receptor alpha (ERalpha) in the human hippocampus in controls and in AD cases. ERalpha immunoreactivity was observed in neurons and glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in the hippocampus both in controls and AD cases. The number and density of GFAP- and ERalpha-positive astrocytes was increased in AD. The number of GFAP-immunoreactive astrocytes, the number of nuclear ERalpha-staining astrocytes, and cytoplasmic ERalpha-staining astrocytes per unit area (1 mm(2)) significantly increased (P < 0.001, P < 0.05, P < 0.05, respectively) in CA1 in AD patients, while the percentage of ERalpha-immunoreactive astrocytes of the two groups did not differ (P > 0.05). These data suggest an important role for ERalpha-mediated effects of estrogens on neurons and astrocytes in the hippocampus of human and AD patients.     

Computerized cognition assessment during acetylcholinesterase inhibitor treatment in Alzheimer’s disease

Wesnes K, Edgar C, Andreasen N, Annas P, Basun H, Lannfelt L, Zetterberg H, Blennow K, Minthon L. Computerized cognition assessment during acetylcholinesterase inhibitor treatment in Alzheimer’s disease.
Acta Neurol Scand: 2010: 122: 270–277.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – Alzheimer’s disease assessment scale‐cognitive subscale (ADAS‐Cog) has become a standard clinical trials outcome for cognition, but has been recognized as deficient in areas including coverage of cognitive domains, sensitivity and standardization. Computerized test batteries may address some of these issues. The cognitive drug research computerized assessment (CDR) system is validated in Alzheimer’s disease (AD). This study was designed to further evaluate validity in relation to ADAS‐Cog, mini mental state examination (MMSE) and cerebrospinal fluid (CSF) biomarkers and psychometric properties, in a population of Alzheimer’s patients on stable anticholinesterase treatment. Materials and methods – Patients completed cognition assessments, CSF and blood sampling at baseline and 6 months later. Data for 65 patients were evaluated. Results – The CDR system demonstrated good psychometric properties in this population. Measures of psychomotor speed showed possible sensitivity to decline over 6 months. Conclusions – There are a number of methodological problems with current cognition assessment methodology for clinical trials. Computerized measures and in particular millisecond reaction time measures, may address many of these issues.     

Zinc takes the center stage: its paradoxical role in Alzheimer’s disease

There is compelling evidence that the etiology of Alzheimer’s disease (AD) involves characteristic amyloid-β (Aβ) deposition, oxidative stress, and anomalous metal–Aβ protein interaction. New studies have implicated redox active metals such as copper, iron, and zinc as key mediating factors in the pathophysiology of Alzheimer’s disease. There is also evidence that drugs with metal chelating properties could produce a significant reversal of amyloid-β plaque deposition in vitro and in vivo. This paper reviews current observations on the etiologic role of zinc in AD. We also discuss the interactions of zinc and copper with Aβ, a factor that purportedly facilitates disease processes. Finally, we review the protective role of zinc against Aβ cytotoxicity and hypothesize how the apparent effect of zinc on AD pathology may be paradoxical, The Zinc Paradox. Indeed, complex pathologic stressors inherent to the Alzheimer’s diseased brain dictate whether or not zinc will be neuroprotective or neurodegenerative. Further research on the zinc paradox in AD is needed in order to elucidate the exact role zinc plays in AD pathogenesis.     

Memory with emotional content,brain amygdala and Alzheimer’s disease

Objectives – A highly adaptive aspect of human memory is the enhancement of explicit, consciously accessible memory by emotional stimuli. We studied the performance of Alzheimer’s disease (AD) patients and elderly controls using a memory battery with emotional content, and we correlated these results with the amygdala and hippocampus volume. Methods – Twenty controls and 20 early AD patients were subjected to the International Affective Picture System (IAPS) and to magnetic resonance imaging‐based volumetric measurements of the medial temporal lobe structures. Results – The results show that excluding control group subjects with 5 or more years of schooling, both groups showed improvement with pleasant or unpleasant figures for the IAPS in an immediate free recall test. Likewise, in a delayed free recall test, both the controls and the AD group showed improvement for pleasant pictures, when education factor was not controlled. The AD group showed improvement in the immediate and delayed free recall test proportional to the medial temporal lobe structures, with no significant clinical correlation between affective valence and amygdala volume. Conclusion – AD patients can correctly identify emotions, at least at this early stage, but this does not improve their memory performance.