阿尔茨海默病和癫:神经变性与网络功能异常相关性研究进展

阿尔茨海默病和癫是神经系统常见疾病,发病机制复杂,缺乏有效治疗手段,是临床神经科学急待解决的重点问题。既往研究显示两者在病因、发病机制、临床表现、治疗等方面均有一定的相关性。文中重点针对阿尔茨海默病和癫共病的病理和发病机制进行的研究,以及对神经变性和网络功能异常的研究进行综述,以探讨阿尔茨海默病和癫研究及治疗新思路。     

家族性皮质肌阵挛震颤伴癫(痫)研究进展

家族性皮质肌阵挛震颤伴癫(痫)是种常染色体显性遗传、成年起病、良性病程的罕见癫(痫)综合征.主要临床表现为肌阵挛样震颤、伴或不伴癫(痫)发作.依据临床表现及神经电生理检查显示肌阵挛样震颤源于大脑皮质可做诊断.抗癫(痫)药物可有效控制患者的肌阵挛样震颤和癫(痫).近期研究已提出数个可能的致病基因位点及机制,文中对其临床表现及发病机制的研究进行综述.     

新型抗癫(痫)药物研究进展

癫(痫)是一种常见的中枢神经系统综合征,严重影响患者生活质量.癫(痫)的治疗目前仍以药物为主,约30％患者为难治性癫(痫).随着对癫(痫)发生发展机制研究深入,以及传统药物升级,许多新型抗癫(痫)药物或具有抗癫(痫)作用的药物不断面市.文中将按照不同的作用机制对新上市的抗癫(痫)药物以及新发现的有抗癫(痫)作用的药物靶点进行介绍.     

托吡酯治疗难治性癫痫32例分析

目的 观察托吡酯治疗难治性癫(痫)的疗效与安全性.方法 对32例难治性癫(痫)患者加用托吡酯治疗进行临床观察研究.结果 15例患者发作频度减少≥50%,8例患者发作频度减少到26%～49%,疗效较佳;各种类型癫(痫)之间发作减少差异不显著;与不同抗癫(痫)药物合用疗效无差异.结论 托吡酯是一种有效的广谱抗癫(痫)药,能与常用抗癫(痫)药合用.     

拉莫三嗪治疗各型癫痫的疗效分析

目的 观察拉莫三嗪治疗各型癫(痫)的疗效.方法 用开放性试验的方法对135例癫(痫)患者进行了添加、添加转单药以及首诊单药的拉莫三嗪治疗,观察其疗效及不良反应.结果 总有效率77.0%,控制率49.6%,对各型癫(痫)均有效.不良反应出现率28.9%.结论 拉莫三嗪是一种安全、有效的抗癫(痫)药物,对各型癫(痫)均有效.     

52例成年难治性癫(痫)患者诊疗现状分析

目的:探索成年难治性癫(痫)患者的诊断、治疗及管理方法.方法:通过对就诊于我科的成年难治性癫(痫)患者的5年临床随访资料进行回顾性分析,了解难治性癫(痫)病情的转归;同时将几种联合用药方案的疗效进行对比,探索最佳方案.结果:确诊为难治性癫(痫)的52例患者中,29例(56％)继续到专科医院就诊;13例(25％)选择到社区或基层医院综合治疗;10例(19％)未规范治疗.经过正规抗癫(痫)治疗者有21例(40％),治疗效果明显,2年内未再发作;31例(60％)病情未能有效控制.结论:难治性癫(痫)患者的就诊、治疗明显影响患者病情的转归,治疗缺口大,依从性差,非医疗因素严重影响其身心健康.应尽快制定规范化的诊疗方式,加大宣传,着力改善癫(痫)患者的生活品质.目前几种常用的二线抗癫(痫)药物对于难治性癫(痫)的疗效比较差异无显著意义.     

《癫(癎)与神经电生理学杂志》2017年度征稿、征订启事

癫(痫)是一种常见的慢性神经系统疾病,属全球性公共卫生问题.在癫(痫)的众多继发因素中,创伤性脑损伤是常见病因之一,同时,创伤性脑损伤后癫(痫)是脑外伤后常见并发症,特别多见于外伤4周以后,即脑外伤后晚期癫(痫)[1].本文介绍1例脑外伤后4个月出现癫(痫)持续状态,后经积极治疗演变为难治性癫(痫)的患者.现报告如下.     

额叶癫(痫)与颞叶癫(痫)的临床与电生理对比分析

目的:对比分析额叶癫(痫)、颞叶癫(痫)发作期临床及脑电图表现.方法:统计2011～2012年视频脑电图(V-EEG)监测中发作的额叶癫(痫)和颞叶癫(痫)各30例,进行病因、影像学以及发作间期、发作期脑电图(EEG)和临床表现对比分析.结果:额叶癫(痫)、颞叶癫(痫)在发作间期、发作期的EEG及临床表现均有各自典型特征,如额叶癫(痫)各年龄段均有发作,颞叶癫(痫)主要集中于成人,额叶癫(痫)发作间期EEG诊断意义不大,额叶癫(痫)发作间期EEG具有一定病灶提示价值,发作期颞叶癫(痫)有先兆者居多且多数为口及消化系统自动症,而额叶癫(痫)多为过度动作,动作夸张且易出现姿势性扭转强直等.结论:V-EEG监测对于具有发作期的额叶癫(痫)、颞叶癫(痫)的诊断具有重要价值.     

脑梗死后癫(痫)发作与TOAST分型的关系

目的 探讨脑梗死后癫(痫)发作的类型、频率、发作时间与TOAST分型的关系,为脑梗死后癫(痢)发作的防治提供帮助.方法 选择2007-11～2010-12在江苏省苏北人民医院神经内科住院的脑梗死后癫(痫)患者86例,并随访至少6个月,观察患者的癫(痫)发作类型、临床特点、头颅MRI或头颅CT结果,并进行TOAST分型.结果 脑梗死后癫(痫)发作患者中LAA 分型者最多,与其他CE、SAA分型差异有统计学意义.LAA分型者合并癫(痫)发作在急性期和恢复期后遗症期差异无统计意义.但CE型及SAA型急性期发作少,与恢复期后遗症期发作差异有统计学意义.随访发现癫(痫)复发者部分性发作明显多于全面性发作.复发患者中LAA最多,但SAA复发比例最高.结论 脑梗死后癫(痫)发作最多见于梗死恢复期及后遗症期,脑梗死后癫(痫)发作在LAA分型中最多见,治疗后癫(痫)复发以部分性发作最多见.SAA分型复发最多,需要长期使用抗癫(痫)药AEDS.脑梗死急性期合并全身性发作类型的癫(痫)相对预后较好,但癫(痫)持续状态例外.     

癫(痫)患者认知功能障碍及生活品质调查

目的:了解癫(痫)患者认知功能损伤的程度和类型及其对患者生活品质(QOL)的影响,分析其认知功能障碍的相关因素.方法:采用配对的前瞻性研究.试验组系2010年3月～20]年3月在重庆医科大学第一附属医院神经内科癫(痫)专病门诊就诊患者,有癫(痫)发作的典型表现和脑电图特征,并由高年资癫(痫)专病医师根据国际抗癫(痫)联盟1981年癫(痫)诊断标准进行判断.对照组来自我院研究生及社区正常人群,年龄、性别、文化程度等均与癫(痫)患者组匹配.在取得知情同意后,试验组和对照组首先进行简易智能状态量表(MMSE)测定,然后用国际通用表格进行听觉词汇回忆测验、数字广度测验、词汇流畅性测试等神经心理学检查,研究癫(痫)患者及正常对照者的认知功能,并进行相关分析.完成后用统一量表进行癫(痫)患者QOL调查,比较试验组与对照组间QOL有无明显差异.结果:试验组和对照组各入选85例.研究发现,与对照组比较,试验组患者在MMSE、词汇流畅性测验中的词汇总数(P＜0.01),听觉词汇回忆测验中的短时延迟回忆、长时延迟回忆及再认回忆(P＜0.01),以及数字广度测验的顺背数及倒背数等方面比较差异有统计学意义(P＜0.01).这就表明癫(痫)患者在词汇记忆、注意和执行能力上有明显损伤.QOL调查也显示癫(痫)患者的日常活动因癫(痫)发作受到了明显的影响.结论:癫(痫)患者的认知功能有明显异常,尤其是在注意力、记忆力以及额叶的认知功能方面可能存在着不同程度的损伤,其QOL也有明显降低.     

Roles of the prostaglandin E2 receptors EP subtypes in Alzheimer’s disease

Neuroinflammation has always been of concern in the pathogenesis of Alzheimer’s disease (AD). As a major inflammatory mediator, prostaglandin E₂(PGE₂) plays an important role in the inflammatory process of AD. Up to now, there is still controversy on the neuroprotective or neurotoxic role of PGE₂. However, the role of PGE₂ in neurodegeneration may be far more complex, due to the 4 EP receptor subtypes. This article aims to summarize the relationship between PGE₂ receptor EP subtypes and AD. It is believed that a better understanding of the PGE₂ receptor EP subtypes may help to clarify the relation between inflammation and AD, and to develop novel therapeutic strategies targeting specific EP receptor for AD treatment.     

Stimulation of PGE receptors EP2 and EP4 protects cultured neurons against oxidative stress and cell death following beta-amyloid exposure

Alzheimer's disease (AD) is associated with gliosis, neuroinflammation and higher levels of prostaglandins. Conflicting roles for cyclooxygenases and prostaglandins in the etiopathology of AD have been reported. We hypothesized that PGE2 signaling through EP2 and EP4 G-protein-coupled receptors could protect against amyloid beta-peptide (Abeta) neurotoxicity by increasing the cAMP signaling cascade. Using primary neuronal cultures, we investigated the presence of EP receptors (EP1-4) and the action of PGE2 and EP receptor agonists on neuronal susceptibility to Abeta1-42 toxicity. Low concentrations (1 microm) of PGE2, butaprost (EP2 agonist), and 1-hydroxy-PGE1 (EP4/EP3 agonist) were neuroprotective against Abeta1-42 toxicity, while sulprostone (EP3/EP1 agonist) at similar doses had no detectable effects. EP2 and EP4 receptor-mediated neuroprotection would involve changes in cAMP levels, as both EP2 and EP4 agonists increased intracellular cAMP concentration by approximately doubling basal levels, and both exhibited neuroprotective actions against Abeta-induced toxicity. The protein kinase A (PKA) inhibitor RpcAMPS significantly attenuated the neuroprotection by butaprost, but not that by 1-hydroxy-PGE1, implying differences between EP2 and EP4 receptor protective mechanisms. Additionally, the increase in reactive oxygen species generated following exposure to Abeta was reduced by stimulation of both EP2 and EP4 receptors. Together, these results indicate that PGE2 can protect neurons against Abeta toxicity by acting on given receptors and stimulating a cascade of intracellular events, including the cAMP-PKA pathway. We propose that development and testing of specific PGE2 receptor agonists downstream of cyclooxygenase could lead to therapeutic applications.     

Encephalitogenic peptide and platelet aggregation in multiple sclerosis

Platelet aggregation (PA) stimulated by encephalitogenic peptide (EP) and PA induced by ADP were measured in 83 multiple sclerosis (MS) patients and 70 control subjects with other neurological diseases (OND). EP-stimulated PA was significantly increased in MS patients as compared with the controls. There was no significant difference in ADP-induced PA between patients with MS and OND. The results are discussed in terms of EP-stimulated platelets playing a role in the pathogenesis of MS by affecting the venular permeability of the brain.     

Alzheimer��s disease is not ��brain aging��: neuropathological, genetic, and epidemiological human studies

Human studies are reviewed concerning whether "aging"-related mechanisms contribute to Alzheimer's disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human "accelerated aging" diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical "dementia" and the subset of dementia cases with AD pathology. Additional aging-associated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an "aging-linked" disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging.     

Tissue inhibitors of matrix metalloproteinases are elevated in cerebrospinal fluid of neurodegenerative diseases

Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of diseases such as Alzheimer's Disease (AD) and amyotrophic lateral sclerosis (ALS). Increased expression of MMP-9 and TIMPs has been reported in postmortem AD and ALS brain tissue, as well as in ALS cerebrospinal fluid (CSF) and plasma. Although individual studies of MMP and TIMP expression in CSF have included AD and ALS samples, there are no studies comparing the expression of these proteins between neurodegenerative diseases. We measured the levels of matrix metalloproteinases (MMPs)-2 and -9 and the tissue inhibitor of MMPs (e.g. TIMP-1 and TIMP-2) in CSF samples from patients with Parkinson's Disease (PD), Huntington's Disease (HD), AD and ALS as compared to age-matched control patients. There was constitutive expression of the proform of gelatinase A (proMMP-2) on zymography gels in all CSF samples. Unexpectedly, there was an additional gelatinolytic band at 130 kDa of unknown etiology in the CSF samples of patients with PD (61% of patients studied), AD (61%), HD (25%) and ALS (39%). Levels of TIMP-1 were significantly elevated in CSF samples from all disease groups. TIMP-2 was significantly increased in CSF of AD and HD patients. MMP-2 levels did not differ significantly between groups. These findings show that TIMPs are elevated in the CSF of patients with neurodegenerative diseases suggesting a potential role of these endogenous inhibitors of matrix metalloproteinases in neurodegenerative diseases.     

Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles "do count" when staging disease severity

There is uncertainty regarding the association of cognitive decline in Alzheimer disease (AD) with classic histopathologic features- neurofibrillary tangles (NFTs) and "neuritic" amyloid plaques (NPs). This uncertainty fuels doubts about the diagnostic importance of NFTs and NPs and leads to confusion regarding hypotheses of AD pathogenesis. Three hundred ninety subjects who underwent longitudinal premortem clinical workup and postmortem quantitative neuropathologic assessment served as the group to address this issue. Subjects with concomitant brain disease(s) were analyzed independently to more accurately assess the contribution of distinct pathologies to cognitive decline. More than 60% of patients of all age groups had important non-AD brain pathologies. However, subjects without superimposed brain diseases showed strong correlations between AD-type pathology counts (NFTs > NPs) and premortem Mini-Mental State Examination scores. The observed correlation was stronger in isocortex than in allocortex and was maintained across age groups including patients older than 90 years. A theoretical model is proposed in which our results are interpreted to support the "amyloid cascade hypothesis" of AD pathogenesis. Our data show that there are many important contributory causes to cognitive decline in older persons. However, NFTs and NPs should not be dismissed as irrelevant in AD based on clinicopathologic correlation.     

Lipid peroxidation and oxidative imbalance: early functional events in Alzheimer's disease

Alzheimer's disease (AD) is a growing public health problem worldwide. Clinically, AD is a progressive neurodegenerative disorder characterized by a global cognitive decline. Accumulating evidence indicates that reactive oxygen species-mediated reactions, particularly of neuronal lipids, are extensive in those AD brain areas directly involved in the disease processes. Traditional views claim that oxidative-mediated tissue injury in the AD brain is the result of neurodegeneration. In recent years, numerous investigations have pointed to the functional importance of oxidative imbalance as a crucial event in mediating AD pathogenesis. The availability of specific and sensitive markers to monitor in vivo oxidative stress, in combination with studies performed in living patients with clinical diagnosis of AD are helping us to elucidate these issues. The evidence we have accumulated so far clearly indicates that oxidative imbalance and subsequent oxidative stress are early events during the evolution of the disease, and secondary to specific mechanism(s) present in AD but not in other neurodegenerative diseases. These new concepts implicate that this phenomenon may play a more important role in AD pathogenesis than previously anticipated, and that any therapeutic intervention targeting oxidative stress should be initiated at the earliest possible stage of the disease.     

Oxidatively modified proteins in Alzheimer’s disease (AD), mild cognitive impairment and animal models of AD: role of Abeta in pathogenesis

Oxidative stress has been implicated in the pathogenesis of a number of diseases including Alzheimer’s disease (AD). The oxidative stress hypothesis of AD pathogenesis, in part, is based on β-amyloid peptide (Aβ)-induced oxidative stress in both in vitro and in vivo studies. Oxidative modification of the protein may induce structural changes in a protein that might lead to its functional impairment. A number of oxidatively modified brain proteins were identified using redox proteomics in AD, mild cognitive impairment (MCI) and Aβ models of AD, which support a role of Aβ in the alteration of a number of biochemical and cellular processes such as energy metabolism, protein degradation, synaptic function, neuritic growth, neurotransmission, cellular defense system, long term potentiation involved in formation of memory, etc. All the redox proteomics-identified brain proteins fit well with the appearance of the three histopathological hallmarks of AD, i.e., synapse loss, amyloid plaque formation and neurofibrillary tangle formation and suggest a direct or indirect association of the identified proteins with the pathological and/or biochemical alterations in AD. Further, Aβ models of AD strongly support the notion that oxidative stress induced by Aβ may be a driving force in AD pathogenesis. Studies conducted on arguably the earliest stage of AD, MCI, may elucidate the mechanism(s) leading to AD pathogenesis by identifying early markers of the disease, and to develop therapeutic strategies to slow or prevent the progression of AD. In this review, we summarized our findings of redox proteomics identified oxidatively modified proteins in AD, MCI and AD models.     

阿尔茨海默病发病机制中血管因素的作用

阿尔茨海默病(AD)是以进行性认知功能障碍和行为损害为特征的中枢神经系统退行性病变,其发病机制目前尚不明确。近年来,越来越多的研究表明血管因素贯穿于AD起病及进展的整个过程。AD相关的血管病变包括慢性低灌注、血管内皮炎症反应、血管新生及血管网异常、神经血管单元等。文中就上述方面的血管因素与AD病理之间的相互作用做一综述。