阿尔茨海默病蛋白质组学研究进展

阿尔茨海默病(AD)是一种临床常见的中枢神经系统变性疾病.目前,全世界约有2430万例痴呆患者,每年新发病例460万[1].     

正电子断层显像技术在阿尔茨海默病中的研究进展

阿尔茨海默病(Alzheimer's disease,AD)是老年人最常见的痴呆类型,为一种进行性神经系统变性疾病[1].其主要神经病理学特征包括神经元纤维缠结(neurofibrillary tangles,NET)、老年斑(senile plaque,Sp)的出现及神经元的减少.迄今为止,AD病因不明,缺乏客观的诊断及有效治疗方法.当AD患者出现临床症状时,往往已处于临床中期阶段,即中度AD,此时治疗效果较差,且很难逆转病情的进展,因此研究者们都在努力寻找早期诊断标记物及疾病修复疗法,结果发现正电子断层显像(PET)技术有望成为实现这个目标的重要手段.研究表明,PET技术可以被用于研究脑代谢变化、各种神经递质系统、炎症过程及蛋白质聚合物(尤其是淀粉样蛋白沉积物)[2].PET利用11C标记的匹兹堡复合物B(11C- PIB)和18F脱氧葡萄糖(18F- FDG)在体显像,可以了解脑内Aβ蛋白分布及葡萄糖代谢情况[3].本文将近年来PET影像技术在AD基础及临床方面的研究情况作一综述.     

阿尔茨海默病发病机制及治疗进展

阿尔茨海默病(AD)是多发于老年人的神经系统变性疾病,临床上以进行性记忆、认知障碍及行为异常为特征,典型的病理学表现为淀粉样蛋白沉积、神经原纤维缠结(NFT)、神经元减少及轴素和突触异常、颗粒空泡变性等.随着社会人口老龄化逐步加剧,阿尔茨海默病发病率呈逐渐上升趋势,其医疗和护理给社会和家庭带来沉重的经济和心理负担[1].即使是调整了其他风险因子,阿尔茨海默病相关的相对死亡风险仍高于其他类型痴呆,尤其是75岁以下的人群[2].因此,对于阿尔茨海默病的研究具有重要临床意义.在本文中,主要概述阿尔茨海默病的发病机制及其治疗进展.     

重视阿尔茨海默病的早期诊断

阿尔茨海默病(AD)的发病率和患病率伴随席卷全球的人口老龄化银色浪潮迅速攀升,每7秒钟世界上就增加1例痴呆患者,每年新增AD患者460万人[1].全球AD患病人数已超过3600万人,2050年将达到1.15亿.2010年全球AD患者的花费超过6000亿美金,占国民生产总值的1％,到2030年还将增加85％[2].美国AD患者已达500万人,患病率占疾病顺位第四,病死率居疾病死亡顺位第五[3].     

阿尔茨海默病中线粒体自噬与Aβ42蛋白相互影响的研究进展

阿尔茨海默病(Alzheimei's disease,AD)是一种以进行性记忆丧失、认知障碍和人格改变为特征的神经退行性疾病,一直以来,β淀粉样蛋白(β amyloid protein,A β)沉积及其神经毒性被普遍认为是AD发病的中心机制[1].近年研究证实,Aβ蛋白沉积与线粒体功能障碍密切相关[2].     

老年性痴呆的早期预防

老年性痴呆,即阿尔茨海默病(Alzheimer's disease,AD),由德国神经病学家Alzheimer首先报道,人们以他的名字来命名该病[1].AD是最常见的老年期痴呆,是严重威胁老年人生命健康的主要疾病之一.据流行病学调查研究发现,我国老年性痴呆的患病率呈现不断上升趋势,在20世纪80年代,我国报告的AD患病率为0.07%～0.46%,20世纪90年代为2.9%,2000年则为4.2%[1][2].     

姜黄素对阿尔茨海默病的治疗作用

姜黄是一种古印第安植物,最早作为调味品一咖喱粉和草药使用.现代医学研究发现,其粉末及提取物姜黄素能治疗各种疾病包括囊性纤维化、压疮、消化道溃疡、大肠癌、乳腺癌、动脉粥样硬化、肝病和关节炎[1].近年来研究发现,姜黄素对各种类型的痴呆和创伤性脑损伤有治疗作用,尤其在预防和治疗阿尔茨海默病(AD)方面具有重要作用.大量的证据表明,生物、金属毒素和异常炎症反应引起的氧化应激、自由基、β淀粉样蛋白、脑功能失调在AD的发病机制中起关键作用.姜黄素具有的抗氧化、抗炎和亲脂活性,能改善AD病人的认知功能,如缩小β淀粉样蛋白斑快、减缓神经元分解、鳌和金属、抗炎、抗氧化、减少小胶质细胞形成、改善AD病人整体记忆等[2].本文对姜黄素治疗AD的活性机制做一综述.     

侧脑室持续灌注和海马急性注射Aβ对食蟹猴的神经毒性作用

阿尔茨海默病(Alzheimer's disease,AD)的病因复杂,尚未明确,关于AD的发病机制已经提出多种假说[1-2].其中,淀粉样蛋白毒性学说因β-淀粉样蛋白(β-Amyloid,Aβ)是构成AD典型病理改变老年斑的核心成份而得到广泛的实验支持.     

皮质下缺血性血管性痴呆的研究进展

阿尔茨海默病(AD)和脑血管病(CVD)是导致老年性痴呆的最常见原因[1].而脑血管病的范畴很大,按受累血管可分为大血管病和小血管病;按疾病性质可分为缺血性卒中和出血性卒中;按病变部位可分为皮质型和皮质下型等.不同损伤原因、部位和性质的脑血管病所导致的血管性痴呆(VaD)其认知功能障碍的差异较大,呈斑片状,不同于阿尔茨海默病的均一表现,为其诊断与治疗和研究带来一定的困难[2].     

Tau蛋白与阿尔茨海默病关系研究进展

阿尔茨海默病(Alzheimer's disease,AD)是一种以进行性痴呆(记忆减退、认知障碍以及人格改变1为临床特征,大脑皮质和海马区域出现细胞外老年斑、细胞内神经元纤维缠结(neurofibrillary tangle,NFT)和营养不良性轴突改变为病理特征的神经变性疾病[1],并且其痴呆症状的严重程度与NFT的多少有关[2].     

Diagnostic Difficulties and Treatment Implications

Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.     

Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

Carbamazepine Efficacy in Adults With Partial and Generalized Tonic-Clonic Seizures

Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.     

Predisposing and Causative Factors in Childhood Epilepsy

Summary: We review information from large studies of defined populations, examining the role of known factors and especially of prenatal and perinatal factors in contributing to nonfebrile seizure disorders of early childhood. We depend especially, but not exclusively, on the recently completed analyses from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, the NCPP. About 4% of children in the NCPP who had at least one non-febrile nonsymptomatic seizure by the age of 7 years had a previous seizure during acute neurologic illness, such as meningitis or during the acute illness after trauma. Many such seizures should potentially be preventable. Of children with seizures, 10% had had a neonatal seizure and 13% had had a febrile seizure. Among the hundreds of prenatal and perinatal factors explored as predictors of childhood seizure disorders, the principal predictors identified were congenital malformations of the fetus, cerebral and noncerebral; family history of certain neurologic disorders; and neonatal seizures. In agreement with the British National Child Development Study, labor and delivery factors in the NCPP appeared to contribute very little to childhood seizure disorders. Maldevelopment, rather than damage at birth to an initially intact nervous system, appeared to be the more common mechanism. Most seizure disorders of early childhood remained unexplained by the large set of prenatal and perinatal characteristics examined.     

Anticonvulsant Drugs and Cognitive Function: A Review of the Literature

Summary: Alterations of cognitive function are separate from disturbances of behavior seen in association with epilepsy. The nature of the cognitive disability may to a certain extent depend on the seizure type. Partial seizures, mainly derived from a temporal lobe focus, impair memory tasks, while generalized seizures seem to have more effect on attentional abilities. A number of studies, reviewed in this paper, suggest that anticonvulsant drugs further impair cognitive function. Maximal impairments are seen in patients receiving polytherapy: rationalization of polytherapy improves cognitive abilities. Studies in children and adults have allowed differentiation of the effects of various commonly used antiepileptic agents. Maximal cognitive deficits are seen with. phenytoin, while phenobarbital and sodium valproate induce moderate disturbances, and carbamazepine seems relatively free from such toxicity. Further research is needed on the interrelationship between types of seizure disorders, types of anticonvulsant medications, and cognitive function.     

Effects of NMD A- and AMPA-Receptor Antagonists on Different Forms of Epileptiform Activity in Rat Temporal Cortex Slices

Summary: Lowering extracellular magnesium induces different patterns of epileptiform activity in rat hippocampus and entorhinal cortex. Short recurrent epileptiform discharges in the hippocampus are stable over time, whereas seizurelike events (SLEs) in the entorhinal cortex, the subiculum, and the neighboring neocortex develop into late recurrent discharges which are not blocked by clinically employed antiepileptic drugs. We tested the sensitivity of the different epileptiform discharge patterns to. /V-methyl-D-aspartate (NMDA)- and non-NMDA-receptor antagonists. As NMDA-receptor antagonist we used dextrorphan, ket-amine, and 2-aminophosphonovalerate (2APV); as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor antagonist we employed the quinoxaline derivative glutamate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The findings show that the different patterns of epileptiform activity, including the late recurrent discharges, are sensitive to all NMDA-receptor antagonists. However, when dextrorphan was employed to suppress seizure-like events, later recurrent discharges did not develop during the remaining time course of the experiment. CNQX reversibly suppressed recurrent discharges in the hippocampus and SLEs in the entorhinal cortex. However, late recurrent discharges become insensitive to CNQX, even at a high concentration of 60 μM m. This finding suggests a prominent role for NMDA receptors in the generation of late recurrent discharges.     

The influence of comorbid depression on seizure severity

PURPOSE: To determine the relation between depressive symptoms and seizure severity among people with epilepsy. METHODS: A postal questionnaire was used to survey a nationwide community sample about seizures and depression. The Seizure Severity Questionnaire (SSQ) assessed the severity and bothersomeness of seizure components. The Centers for Epidemiological Studies-Depression scale categorized levels of depression. RESULTS: Respondents categorized as having current severe (SEV, n = 166), mild-moderate (MOD, n = 74), or no depression (NO, n = 443) differed significantly in SSQ scores (all p < 0.0001). People with SEV or MOD reported significantly worse problems than did those with NO depression for overall seizure recovery (mean, 5.3, 4.9, 4.5, respectively); overall severity (5.0, 4.5, 4.2); and overall seizure bother (5.3, 4.8, 4.4) (all p < 0.005). Cognitive, emotional, and physical aspects of seizure recovery also were rated worse among people with SEV than with NO depression (all p < 0.05). Symptoms of depression were significantly correlated with higher levels of all components of generalized tonic-clonic seizure severity (r = 0.33-0.48; all p < 0.0001), and partial seizures (r = 0.31-0.38; all p < 0.01). CONCLUSIONS: Clinically depressed people with epilepsy reported higher levels of perceived severity and bother from seizures, as well as greater problems with overall seizure recovery than did nondepressed people experiencing similar types of seizures. The pervasive influence of depressive symptoms on reports of seizure activity suggests that people with epilepsy should be screened for depression. These data highlight the importance of detecting and treating depression among people with epilepsy.     

Une phénoménologie de la dépendance à l'alcool. Une expérience primordiale de la « nostrité »

The phenomenological approach to alcoholism interestingly focuses on specific dynamics of interpersonal relationships displaying the founding of the Self from a primary “us” and its original basis in the human feast. Priorities for treatment intervention recommend to involve social setting and relationships of the patients, reaching their active participation to a motivational and long term group treatment, underlying the specific therapeutic effect of world exchanges. Biopsychosocial determination of alcoholism could be primarily based on components of interpersonal relationships. Regarding social background, drinking is one of the most famous supports for the achievement of the feast, a founding marker of present time. Taking an existential point of view, the feast appears as the heart of mankind because it presents a primary “us”, a plural state which indicates the beginning and founding of the Self from the others. During the feast, we regularly have to reach our Self from the “us” while avoiding two main dangers, drunkenness, an increase in the dizziness of upright verticality, and addiction, an opposite vertical surrender to alcohol and falling into in the alcoholic relapse, both situations imply a spatial domination and the disappearance of others. Treatment programs of alcohol addicts need to integrate the necessity of reaching the existential basic trust from the support of a group to the appropriation of the community which can be defined as an original “usness”.