Biochemical assay of Alzheimer's disease--associated protein(s) in human brain tissue. A clinical study

The concentration of Alzheimer's disease-associated protein (ADAP) was measured in postmortem brain tissue samples of temporal or frontal cortex from 111 human brains using a sandwich immunoassay. Alzheimer's disease-associated protein has three major ALZ-50-reactive subunits, including A-68. This assay utilizes ALZ-50 and a rabbit antibody raised against a highly ADAP-enriched brain protein fraction. The frequently observed cross-reactivity of ALZ-50 with normal brain components in direct immunoassays is minimized by this configuration. There were 27 normal controls, 28 neurologic disease controls, and 56 Alzheimer's disease cases. The normal control and neurologic disease control cases had essentially no detectable level of ADAP, while ADAP was clearly detected in 85.7% of the Alzheimer's disease cases. Clinical dementia, neuritic plaques, and old age per se are not correlated with increased ADAP levels. This biochemical assay of ADAP may prove to be helpful as an adjunct in the clinicopathologic diagnosis of Alzheimer's disease.     

Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported

Clinically diagnosed Alzheimer's disease and other dementing illnesses were assessed in a geographically defined US community. Of 3623 persons (80.8% of all community residents over 65 years of age) who had brief memory testing in their homes, a stratified sample of 467 persons underwent neurological, neuropsychological, and laboratory examination. Prevalence rates of Alzheimer's disease were calculated for the community population from the sample undergoing clinical evaluation. Of those over the age of 65 years, an estimated 10.3% (95% confidence limits, 8.1% and 12.5%) had probable Alzheimer's disease. This prevalence rate was strongly associated with age. Of those 65 to 74 years old, 3.0% (95% confidence limits, 0.8 and 5.2) had probable Alzheimer's disease, compared with 18.7% (95% confidence limits, 13.2 and 24.2) of those 75 to 84 years old and 47.2% (95% confidence limits, 37.0 and 63.2) of those over 85 years. Other dementing conditions were uncommon. Of community residents with moderate or severe cognitive impairment, 84.1% had clinically diagnosed Alzheimer's disease as the only probable diagnosis. These data suggest that clinically diagnosed Alzheimer's disease is a common condition and that its public health impact will continue to increase with increasing longevity of the population.     

Phosphorylated neurofilament epitopes in the achromasic neurons of corticonigral degeneration.

By employing monoclonal phosphorylated neurofilaments antibody, we studied the abnormally pale-staining neurons in 3 cases of corticonigral degeneration by the avidin-biotin immunoperoxidase method. For comparison, the central chromatolysis in anterior horn cells secondary to cervical spine fracture and "ballooned" neurons in a case of Pick's disease and a case of Alzheimer's disease were studied with similar procedure. Achromasic neurons in the case of corticonigral degeneration and ballooned neurons in Pick's disease and Alzheimer's disease showed positive immunostaining, while neurons with central chromatolysis secondary to axonal injury did not. Our observations show that the achromasic neurons in corticonigral degeneration contain phosphorylated neurofilaments which share common antigenic characteristics with ballooned neurons in Pick's disease and Alzheimer's disease. The absence of positive immunostaining in reactive central chromatolysis suggests that despite the similarities in appearance with the usual histopathologic stains this cytoplasmic change is pathogenetically different from that in the other neuronal disorders mentioned above.

     

Alzheimer's disease: early diagnosis and treatment

With ageing of populations, the worldwide population of persons with dementia will reach over 81 million by 2040, of which the most common cause is Alzheimer's disease. In recent years, there have been major advances in the understanding of its pathogenesis, methods to diagnose it, and treatment. Magnetic resonance brain imaging, cerebrospinal fluid biomarkers, and Pittsburgh compound B and fluorodeoxyglucose positron emission tomography of the brain can facilitate an accurate diagnosis of Alzheimer's disease in its early stage, and diagnose the mild cognitive impairment stage of Alzheimer's disease. At present, only symptomatic but not disease-modifying drug treatments are available. Donepezil, rivastigmine and galantamine are the currently approved cholinesterase inhibitors for the treatment of mild, moderate, and severe Alzheimer's disease. Overall, cholinesterase inhibitors show beneficial effects on cognition, activity of daily living, behaviour, and overall clinical rating. Memantine is another symptomatic treatment for moderate-to-severe Alzheimer's disease patients. It has a small beneficial effect on cognition, activity of daily living, behaviour, and overall clinical rating. Vitamin E has antioxidant properties, and may be used in some Alzheimer's disease patients without vascular risk factors. Concurrent non-pharmacological and psychosocial management of patients and their caregivers have a very important role. Disease-modifying therapies are still under development, whilst immunotherapy may be a viable option in the near future.     

阿尔茨海默病和内皮祖细胞的研究进展

痴呆最常见的病因是阿尔茨海默病(AD),传统观点认为AD是神经系统变性疾病,而近年来内皮功能异常在其发生、发展中的作用越来越受到关注。外周血内皮祖细胞(EPCs)是能够直接反映内皮功能的指标之一,其数目和功能的异常提示血管内皮功能失调及血管修复能力下降。EPCs数目和功能异常所致的脑血管内皮损害和修复能力下降、脑灌注不良可能与AD患者的认知功能障碍有关。因此深入研究AD和外周血EPCs的关系,将有利于进一步揭示AD的发病机制,为其防治提供新的思路。     

11: disorders of memory and intellect.

The clinical approach to the patient with a suspected disorder of memory and intellect is to establish whether it is dementia, which parts of the brain are affected, what is the cause, what is the prognosis, and what can be done about it. The diagnosis of dementia usually requires the involvement of memory and at least one other cognitive system. Delirium and depression are important differential diagnoses. Patients with dementia should usually have some simple investigations after a careful history-taking and examination to identify "reversible" causes. The commonest cause of dementia is Alzheimer's disease, in which short-term memory disturbance is usually prominent. Other causes of dementia include cerebrovascular disease, Lewy-body disease and Pick's disease. There is now hope for patients with Alzheimer's disease (which can be treated with some success with cholinesterase inhibitors) and patients with vascular dementia, in whom aggressive control of causal risk factors may retard progression.     

Alzheimer氏病74例临床资料分析

本文对74例Alzheimer氏病的临床资料进行了分析探讨。认为对其分型是深入研究的前提,同时认为最先出现的症状为记忆障碍,早期出现的引人注目的症状为个性改变。CT和气脑造影对诊断有重要意义。应注意同老年期抑郁症和多发性梗塞性痴呆相鉴别。指出,加强护理,减少并发症是目前延长本病患者生命的唯一方法。     

Over-expression of c-fos mRNA in the hippocampal neurons in Alzheimer's disease.

OBJECTIVE: To analyze the relationship between the proto-oncogene c-fos change and neuronal degeneration in the hippocampus of the patients with Alzheimer's disease. METHODS: The post mortem human hippocampal tissues were divided into three groups, namely, the aged, the young and Alzheimer's disease (AD) groups. Each group consisted of 10 patients. The diagnosis of AD was made by clinical manifestation and argentatine (Bodían) staining. Patients of both the young and the aged groups had no neurological disorders. The proto-oncogene c-fos mRNA was investigated in the hippocampal neurons using the method of in situ hybridization. RESULTS: The optical density of stained area and the integral within proto-oncogene c-fos mRNA revealed a significant increase in the hippocampal neurons in cases of Alzheimer's disease as compared with the controls. CONCLUSIONS: The over-expression of the proto-oncogene c-fos might play a role in the pathological process of Alzheimer's disease. These changes might result from a suffering stage of the hippocampal neurons or from a compensatory mechanism in the surviving neurons which are not yet affected-by the pathological process.     

细胞自噬作用在阿尔茨海默病治疗过程中的作用

阿尔茨海默病(Alzheimer’s disease,AD),是一种以进行性认知障碍和记忆力损害为主的脑部神经退行性疾病。在该疾病中,其发病机制尚未明确,因此目前仍无有效的治疗方法。自噬在清除异常积聚的蛋白以及受损细胞器、维持细胞内稳态和细胞代谢中扮演重要角色。本文对细胞自噬作用在阿尔兹海默病治疗过程中的作用进行了综述,以期为发现阿尔兹海默病的新的治疗靶点提供参考。     

The decline and resurgence of vascular dementia.

Arteriosclerotic narrowing of cerebral arteries was once viewed as the key to mental decline. As Alzheimer's disease gained recognition and the concept of multi-infarct dementia achieved acceptance, vascular dementia came to be regarded as uncommon. The changing nature of cerebral vascular disease, the aging of the population and the widespread use of brain imaging techniques have brought new prominence to vascular dementia, chiefly in the form of an epidemic of "Binswanger's disease". Growing evidence suggests that not only grey matter lesions but also white matter lesions contribute to dementia, that vascular factors commonly coexist and interact with Alzheimer changes and that Alzheimer's disease has a vascular and potentially treatable component. Vascular dementia needs to be redefined, reappraised and reinvestigated.     

阿尔茨海默病外周血早期生物标志物的研究进展

阿尔茨海默病发病隐匿,在痴呆症状出现前数十年,体内已产生一系列病理变化,一旦进入痴呆期,目前尚无理想的药物和疗法可缓解病情。其与衰老呈正相关,年龄越大,患病风险越高。筛选合适的生物标志物进行早期诊断、早预防、早发现、早治疗,对预防和延缓阿尔茨海默病的发展有着重要意义。外周血生物标志物易采集、易检测、可重复,是最理想的生物标志物来源。本文根据阿尔茨海默病经典的β淀粉样蛋白（Aβ）和Tau蛋白机制,梳理了部分外周血中潜在的生物标志物。     

脑源性神经营养因子与阿尔茨海默病的关系

脑源性神经营养因子(BDNF)是一种在成年哺乳类大脑分布广泛的小二聚体蛋白，结构类似神经生长因子。BDNF可促进与阿尔茨海默病(AD)有关神经元(包括海马和皮质神经元，隔核和基底前脑胆碱能神经元和黑质多巴胺神经元)的存活。总结BDNF的分子和细胞生物学方面的工作，包括细胞内的运输，合成和释放的调节，突触水平的变化，对近年有关BDNF’-及其受体(TrkB)与AD神经病理生理学关系的研究进展作一综述。     

胰岛素与阿尔茨海默病

近年来，阿尔茨海默病（AD）的发病率呈明显增加的趋势，但其发病机制仍不明确。胰岛素及其受体被认为可能与AD的发病有关。文章就胰岛素与脑内葡萄糖代谢的关系以及胰岛素、胰岛素受体和胰岛素抵抗与AD发病的关系及其可能机制进行综述，并介绍AD的治疗进展。     

Effect of tetrahydroaminoacridine on cognition, function and behaviour in Alzheimer's disease.

OBJECTIVE: To determine the efficacy of tetrahydroaminoacridine (THA) in Alzheimer's disease. DESIGN: Randomized, double-blind, multiple crossover trial with three treatment periods, each consisting of 3 weeks of active drug therapy and 3 weeks of placebo administration. SETTING: Referral-based geriatric practice in a community hospital. PATIENTS: Thirty-four patients with moderate to severe Alzheimer's disease. Subjects were included if they had stage 3 to 6 disease (as determined by the Reisberg scale) and had not been taking psychotropic drugs for at least 1 month and if informed consent had been obtained from the patients and their next of kin. INTERVENTIONS: Fifty to 100 mg of THA daily and matched placebo. RESULTS: Of the initial 34 patients 14 experienced liver toxicity and 3 gastrointestinal side effects during the study; however, all 22 who completed the study were able to tolerate at least the minimum dose. For the 22 patients there was no clinically or statistically significant effect of THA on cognition, functional status or behaviour. The results for individual patients showed no subgroup of THA-responsive patients. CONCLUSION: THA has no clinically important benefits in Alzheimer's disease and is associated with appreciable toxic effects.     

Alzheimer病与缺血性脑血管病相关性的研究进展

近年来,随着对Alzheimer病发病机制及相关因素的深入研究,发现Alzheimer病与缺血性脑血管病之间有着共同的发病基础,缺血性脑血管病的发生可能参与或促进了Alzheimer病的发生和发展。在本文中作者对二者的相关性研究进行综述,为该病的诊治和预防提供新的思路。     

抗糖尿病药物:一种可能治疗阿尔茨海默病的新方法

随着世界人口老龄化程度的加剧,糖尿病和阿尔茨海默病已成为日益严重的公众健康问题.越来越多的研究显示这两种疾病存在着密切联系,因此,研究它们的共同致病机制以及相互联系对这两种疾病的预防和治疗具有重要意义.本文总结了近几年来在糖尿病和阿尔茨海默病相关性研究方面的最新进展,并对抗糖尿病药物在治疗阿尔茨海默病方面的应用进行了综...     

Determining the cause of dementia

In conclusion, dementia remains a major health problem among the elderly. Although Alzheimer's disease is now recognized as the major cause of dementia, there exist many other conditions which can be easily confused with Alzheimer's disease and for which specific treatment is available. Despite inherent problems in clinically diagnosing Alzheimer's disease, a careful and organized approach to the evaluation of the dementia patient will usually allow the clinician to determine the specific cause of the dementia and with a fairly high degree of accuracy.     

阿尔茨海默病的发病机制和动物模型研究进展

阿尔茨海默病（Alzheimer's disease,AD）是一种慢性中枢神经系统退行性疾病。AD的病因不明、发病机制复杂,因此动物模型的建立对探索其发病机制及寻找防治疾病的药物具有重要作用。在动物模型中,转基因小鼠模型和转基因果蝇模型已成为研究热点。本文就阿尔茨海默病的发病机制和动物模型的研究现状进行综述。     

Positron emission tomography in patients with clinically diagnosed Alzheimer's disease.

Fourteen patients who had clinically diagnosed Alzheimer's disease with mild to severe dementia (mean age 69.1 years) were evaluated by calculation of local cerebral metabolic rate for glucose (LCMR-gl) based on uptake of 18F-2-fluoro-2-deoxyglucose (FDG) detected with positron emission tomography (PET). PET scanning showed that the patients had significantly lower LCMR-gl values than 11 age-matched neurologically normal volunteers (mean age 66.3 years). The differences were most marked in the temporal cortex, followed by the frontal, parietal and occipital cortex. In each case the LCMR-gl value was below the lowest control value in at least one cortical area and usually in several; the reduction in LCMR-gl and the number of regions involved in the patients increased with the severity of the dementia. Deficits noted in neuropsychologic testing generally correlated with those predicted from loss of regional cortical metabolism. The patients with Alzheimer's disease were also examined with magnetic resonance imaging, computed tomography or both; the degree of atrophy found showed only a poor correlation with the neuropsychologic deficit. Significant atrophy was also noted in some of the controls. A detailed analysis of LCMR-gl values in selected cerebral regions of various sizes refuted the hypothesis that the reduction in cortical glucose metabolism in Alzheimer's disease is due to the filling by metabolically inert cerebrospinal fluid of space created by tissue atrophy.     

Perspectives on the etiology of Alzheimer's disease

There is a lack of consensus among investigators concerning the etiology of Alzheimer's disease. Clues are not lacking, however, and we have assessed them in a broad biologic context. This inquiry has led us to regard Alzheimer's disease as a multifactorial disorder in which a putative infective agent is an essential element. Despite seeming competition among current hypotheses, there is overall unity. The concept that Down's syndrome is a congenital form of Alzheimer's disease and that both conditions are the result of a ubiquitous infective pathogen that affects genetically susceptible individuals offers the broadest unification. In both conditions slow infection develops against the background of aging. Indirect evidence involving immunologic and other biologic phenomena supports the postulated infectious origin. Overlapping pathologic and clinical features of Alzheimer's disease and the known transmissible encephalopathies suggest a similar pathogenesis.