Osthole improves synaptic plasticity in the hippocampus and cognitive function of Alzheimer’s disease rats via regulating glutamate

Osthole, an effective monomer in Chinese medicinal herbs, can cross the blood-brain barrier and protect against brain injury, with few toxic effects. In this study, a rat model of Alzheimer’s disease was established after intracerebroventricular injection of β-amyloid peptide (25-35). Subsequently, the rats were intraperitoneally treated with osthole (12.5 or 25.0 mg/kg) for 14 successive days. Results showed that osthole treatment significantly improved cognitive impairment and protected hippocampal neurons of Alzheimer’s disease rats. Also, osthole treatment alleviated suppressed long-term potentiation in the hippocampus of Alzheimer’s disease rats. In these osthole-treated Alzheimer’s disease rats, the level of glutamate decreased, but there was no significant change in γ-amino-butyric acid. These experimental findings suggest that osthole can improve learning and memory impairment, and increase synaptic plasticity in Alzheimer’s disease rats. These effects of osthole may be because of its regulation of central glutamate and γ-amino-butyric acid levels.     

Differential inhibition of acetylcholinesterase molecular forms in normal and Alzheimer disease brain.

Molecular forms of acetylcholinesterase were studied in three brain regions from Alzheimer disease patients and non-demented, age-matched controls. In Alzheimer disease patients, the membrane-bound G4 form was decreased in frontal (-71%) and parietal cortex (-45%) and in the caudate-putamen (-47%) from control levels. We also found a decrease of aqueous-soluble acetylcholinesterase molecular forms in the aqueous-soluble acetylcholinesterase molecular forms in the caudate-putamen region. The effect of three clinically significant acetylcholinesterase inhibitors, heptyl-physostigmine, physostigmine and edrophonium, on aqueous-soluble acetylcholinesterase molecular forms of the caudate-putamen was investigated. Heptyl-physostigmine, a physostigmine analogue, showed preferential inhibition for the G1 form. On the contrary, edrophonium inhibited the G4 form more potently than the G1 form. Physostigmine inhibited both forms with similar potency. The clinical implications of selective acetylcholinesterase inhibitors are discussed.     

Brain acetylcholinesterase activity in Alzheimer disease measured by positron emission tomography

Brain acetylcholinesterase activity was measured in 14 patients with Alzheimer disease and 14 age-matched control subjects by positron emission tomography with a radioactive acetylcholine analogue. Kinetic analysis was performed to calculate k3, an index of acetylcholinesterase activity. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala of all patients with Alzheimer disease, suggesting a loss of cholinergic innervation from the basal forebrain. Most profound reductions of k3 values were observed in the temporal (-30%) and parietal cortices (-31%), although reductions of k3 values were relatively uniform in the cerebral neocortex. This technique may be a powerful tool for early diagnosis of Alzheimer disease and also for therapeutic monitoring of acetylcholinesterase inhibitors in Alzheimer disease.     

Effects of medicinal plants on Alzheimer's disease and memory deficits

Alzheimer's disease is an age-related neurodegenerative disorder characterized by memory deficits. Various studies have been carried out to find therapeutic approaches for Alzheimer's disease. However, the proper treatment option is still not available. There is no cure for Alzheimer's disease, but symptomatic treatment may improve the memory and other dementia related problems. Traditional medicine is practiced worldwide as memory enhancer since ancient times. Natural therapy including herbs and medicinal plants has been used in the treatment of memory deficits such as dementia, amnesia, as well as Alzheimer s disease since a long time. Medicinal plants have been used in different systems of medicine, particularly Unani system of medicines and exhibited their powerful roles in the management and cure of memory disorders. Most of herbs and plants have been chemically evaluated and their efficacy has also been proven in clinical trials. However, the underlying mechanisms of actions are still on the way. In this paper, we have reviewed the role of different medicinal plants that play an important role in the treatment of Alzheimer s disease and memory deficits using conventional herbal therapy.     

姜黄素和安理申联合治疗老年性痴呆研究

目的 探讨联合应用姜黄素和安理申对老年性痴呆患者认知功能和行为能力的改善作用.方法 收集老年性痴呆患者90例,随机分为3个组,姜黄素和安理申联合治疗组30例,安理申治疗组30例,空白对照组30例.空白对照组不使用治疗痴呆药物.3组患者分别在治疗前和治疗3、6个月后进行MMSE评分、ADL评分的测评.结果 姜黄素和安理申联合治疗组患者治疗后认知、行为能力较安理申治疗组改善明显(P＜0.01).结论 姜黄素和安理申联合治疗对老年性痴呆患者认知、行为能力有显著改善作用.     

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.     

Yizhijiannao Granule and a combination of its effective monomers,icariin and Panax notoginseng saponins,inhibit early PC12 cell apoptosis induced by beta-amyloid(25-35)

One of our previous studies showed that Yizhijiannao Granule,a compound Chinese medicine, effectively improved the clinical symptoms of Alzheimer’s disease.In the present study,we established a model of Alzheimer’s disease using beta-amyloid(25-35)in PC12 cells,and treated the cells with Yizhijiannao Granule and its four monomers,i.e.,icariin,catechin,Panax notoginseng saponins,and eleutheroside E.Flow cytometry showed that Yizhijiannao Granule-containing serum, icariin,Panax notoginseng saponins,and icariin+Panax notoginseng saponins were protective against beta-amyloid(25-35)-induced injury in PC12 cells.Icariin in combination with Panax notoginseng saponins significantly inhibited early apoptosis of PC12 cells with beta-amyloid (25-35)-induced injury compared to icariin or Panax notoginseng saponins alone.The effects of icariin+Panax notoginseng saponins were similar to the effects of Yizhijiannao Granule.The findings indicate that two of the effective monomers of Yizhijiannao Granule,icariin and Panax notoginseng saponins,can synergistically inhibit early apoptosis of PC12 cells induced by beta-amyloid(25-35).     

Commentary on “Health economics and the value of therapy in Alzheimer’s disease.” Value therapy for Alzheimer’s disease—A European perspective

The overall goal of value therapy is to provide the most efficient use of resources, taking into account both the cost and the value derived from a given technology or drug, and to assist in healthcare decision-making, because both cost and effectiveness are considered. After a short review of European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP) recommendations for the development of medications for Alzheimer’s disease, we focus on the evidence with respect to cost and benefits obtained so far with acetylcholinesterase inhibitor (AChEI) and Memantine in the treatment of Alzheimer’s disease. We then analyze the recommendations developed by professionals for the treatment of Alzheimer’s disease at the national level in European countries, and finally we discuss how to utilize this process more homogenously in the future to assess value therapeutic values in Alzheimer’s disease.     

多模态影像学在不同阶段阿尔茨海默病中应用研究

目的 评估多模态影像学技术在不同阶段阿尔茨海默病患者中的应用价值.方法 募集2016年12月1日至2018年11月30日就诊于包头市中心医院神经内科受试者共56例,根据入组标准及排除标准,纳入轻度认知功能障碍期者(MCI组)18例、痴呆阶段阿尔茨海默病者(AD组)18例以及与上述病例相匹配健康志愿者(正常组)20例.所...     

The stability of AQT processing speed,ADAS‐Cog and MMSE during acetylcholinesterase inhibitor treatment in Alzheimer’s disease

Wiig EH, Annas P, Basun H, Andreasen N, Lannfelt L, Zetterberg H, Blennow K, Minthon L. The stability of AQT processing speed, ADAS‐Cog and MMSE during acetylcholinesterase inhibitor treatment in Alzheimer’s disease.
Acta Neurol Scand: 2010: 121: 186–193.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – To explore the longitudinal stability of measures of cognition during treatment with acetylcholinesterase inhibitors (AchEI) in patients with Alzheimer’s disease (AD). Materials and methods – Cognitive status was measured in a cohort of 60 patients at 6 months after initiation of treatment with AchEI (baseline) and after an additional 6 months of treatment (endpoint). A Quick Test of Cognitive Speed (AQT), Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog), and MMSE were administered concurrently. Results – Correlations (ρ) between age and AQT processing speed were non‐significant, but were significant for ADAS‐Cog and Mini Mental State Examination (MMSE). AQT and ADAS‐Cog means did not differ significantly between baseline and endpoint. There was a small, significant reduction in MMSE point scores. Measures of stability (Spearman’s ρ) were moderate‐to‐high for all tests. Means for subgroups did not differ as a function of medication type. Conclusions – AQT processing speed, ADAS‐Cog, and MMSE measures proved stable during the second 6 months of treatment with AChEI.     

Debrisoquine metabolism in Chinese patients with Alzheimer’s and Parkinson’s diseases

We determined the oxidative phenotype and metabolic ratio of debrisoquine in 96 Chinese patients with Alzheimer’s disease (n=12), Parkinson’s disease (n=55), and using patients with stroke and cervical spondylosis as controls (n=29). We did not find any difference in debrisoquine metabolic phenotype among Parkinson’s disease, Alzheimer’s disease, and control patients as judged by chi-square analysis. In addition, the metabolic ratio of all our patients was less than 12.6. The result suggested that Chinese patients with Parkinson’s disease and Alzheimer’s disease metabolize debrisoquine at a velocity not different from that of their Western counterparts even though the frequency distribution of debrisoquine metabolism phenotyping in these two populations is quite different.     

Matrix metalloproteinase 14 modulates diabetes and Alzheimer’s disease cross-talk: a meta-analysis

Diabetes mellitus is associated with dementia, but whether diabetes is associated with Alzheimer’s disease remains controversial. Alzheimer’s disease is characterized by amyloid beta aggregation. We hypothesized that genes, involved in amyloid beta degradation, may be altered due to diabetes and thus participate in progression of Alzheimer’s disease. Expression profiling of amyloid beta-degrading enzymes in streptozotocin-induced diabetic mice and their correlation with expression of amyloid precursor protein in hippocampus of Alzheimer’s disease patients were accessed. We found that matrix metalloproteinase 14 decreased in brain but not in other tissues of streptozotocin-induced diabetic mice, and was negatively correlated with expression of amyloid precursor protein in hippocampus of Alzheimer’s disease patients. These findings suggested matrix metalloproteinase 14 may link insulin-deficient diabetes to Alzheimer’s disease.     

What is the new target inhibiting the progression of Alzheimer’s disease？

To stop the progression of Alzheimer＇s disease in the early stage, it is necessary to identify new therapeutic targets. We examined striatal-enriched phosphatase 61 expression in the brain tissues of 12-month-old APPswe/PSEN1dE9 transgenic mice. Immunohistochemistry showed that striatal-enriched phosphatase 61 protein expression was significantly increased but phosphorylated N-methyl-D-aspartate receptor 2B levels were significantly decreased in the cortex and hippocampus of APPswe/PSEN1dE9 transgenic mice. Western blotting of a cell model of Alzheimer＇s disease consisting of amyloid-beta peptide （1-42）-treated C57BL/6 mouse cortical neurons in vitro showed that valeric acid （AP5）, an N-methyl-D-aspartate receptor antagonist, significantly inhibited amyloidbeta 1-42-induced increased activity of striatal-enriched phosphatase 61. In addition, the phosphorylation of N-methyl-D-aspartate receptor 2B at Tyr1472 was impaired in amyloid-beta 1-42-treated cortical neurons, but knockdown of striatal-enriched phosphatase 61 enhanced the phosphorylation of N-methyl-D-aspartate receptor 2B. Collectively, these findings indicate that striatal-enriched phosphatase 61 can disturb N-methyl-D-aspartate receptor transport and inhibit the progression of learning and study disturbances induced by Alzheimer＇s disease. Thus, striatal-enriched phosphatase 61 may represent a new target for inhibiting the progression of Alzheimer＇s disease.     

Drug development status for Alzheimer’s disease: present scenario

Recent advances in the understanding of Alzheimer’s disease pathogenesis have led to the development of numerous compounds that might ameliorate the disease process. Research in the field of Alzheimer’s disease therapy has been partly successful in terms of developing symptomatic treatments, but also had several failures in terms of developing disease-modifying therapies. These successes and failures have led to a debate about the potential deficiencies in our understanding of the pathogenesis of Alzheimer’s disease and potential pitfalls in diagnosis, choice of therapeutic targets, development of drug candidates, and design of clinical trials. Many clinical and experimental studies are ongoing, but we need to acknowledge that a single cure for Alzheimer’s disease is unlikely to be found and that the approach to drug development for this disorder needs to be reconsidered. Preclinical research is constantly providing us with new information on pieces of the complex Alzheimer’s disease puzzle, and an analysis of this information might reveal patterns of pharmacological interactions instead of single potential drug targets. Several promising randomized controlled trials are ongoing, and the increased collaboration between pharmaceutical companies, basic researchers, and clinical researchers has the potential to bring us closer to developing an optimum pharmaceutical approach for the treatment of Alzheimer’s disease.     

Oscillatory connectivity as a diagnostic marker of dementia due to Alzheimer’s disease

ObjectiveQuantitative EEG power has not been as effective in discriminating between healthy aging and Alzheimer’s disease as conventional biomarkers. But EEG coherence has shown promising results in small samples. The overall aim was to evaluate if EEG connectivity markers can discriminate between Alzheimer’s disease, mild cognitive impairment, and healthy aging and to explore the early underlying changes in coherence.MethodsEEGs were included in the analysis from 135 healthy controls, 117 patients with mild cognitive impairment, and 117 patients with Alzheimer’s disease from six Nordic memory clinics. Principal component analysis was performed before multinomial regression.ResultsWe found classification accuracies of above 95% based on coherence, imaginary part of coherence, and the weighted phase-lag index. The most prominent changes in coherence were decreased alpha coherence in Alzheimer’s disease, which was correlated to the scores of the 10-word test in the Consortium to Establish a Registry for Alzheimer’s Disease battery.ConclusionsThe diagnostic accuracies for EEG connectivity measures are higher than findings from studies investigating EEG power and conventional Alzheimer's disease biomarkers. Furthermore, decreased alpha coherence is one of the earliest changes in Alzheimer’s disease and associated with memory function.SignificanceEEG connectivity measures may be useful supplementary diagnostic classifiers.     

A short review of cognitive and functional neuroimaging studies of cholinergic drugs: implications for therapeutic potentials

In the last 20 years a cholinergic dysfunction has been the major working hypothesis for the pharmacology of memory disorders. Cholinergic antagonists and lesions impair and different classes of cholinomimetics (i.e. acetylcholine precursors, cholinergic agonists and acetylcholinesterase inhibitors) enhance attention and memory in experiment animals, healthy human subjects and Alzheimer disease patients. In addition, acetylcholinesterase inhibitors improve different cognitive (i.e. visuospatial and verbal) functions in a variety of unrelated disorders such as dementia with Lewy bodies, Parkinson disease, multiple sclerosis, schizoaffective disorders, iatrogenic memory loss, traumatic brain injury, hyperactivity attention disorder and, as we recently reported, vascular dementia and mild cognitive impairment. In animals, different cholinomimetics dose-dependently increased regional cerebral metabolic rates for glucose (rCMRglc) and regional blood flow (rCBF), two indices of neuronal function, more markedly in subcortical regions (i.e. thalamus, hippocampus and visual system nuclei). In both healthy human subjects and Alzheimer disease patients acetylcholinesterase inhibitors increased rCMRglc and rCBF in subcortical and cortical brain regions at rest but attenuated rCBF increases during cognitive performances. Hence, acetylcholinesterase inhibitors may enhance cognition and rCMRglc by acting primarily on subcortical regions that are involved in attentional (i.e. thalamus) and memory (i.e. hippocampus) processes; such an effect probably is not specific for Alzheimer disease and can be beneficial in patients suffering from a wide array of neuropsychiatric disorders.     

Total intracranial and lateral ventricle volumes measurement in Alzheimer’s disease: A methodological study

Measuring of brain and its compartments’ sizes from magnetic resonance (MR) images is an effective way to assess disease progression in neurodegenerative disorders, particularly Alzheimer’s disease (AD). The objective of this study was to compare total intracranial volume (TIV) and lateral ventricle volume (LVV) in patients with Alzheimer’s disease with those in elderly control subjects, and to compare an automated method (automatic lateral ventricle delineation [ALVIN]) and a manual method (ImageJ). MRI of the brain was performed on 20 patients with Alzheimer’s disease and 18 control subjects. The TIV was calculated by a manual method and the LVV was calculated by using two methods: an automated and manual method. We found a significant increase in LVVs in Alzheimer’s disease patients compared to control subjects, but no difference in TIV between the two groups. A perfect agreement, with 0.989 (0.973–0.996) intraclass correlation coefficient (ICC) and 0.978 (0.946–0.991) concordance correlation coefficient (CCC), was observed between the manual and automatic lateral ventricle measurements in Alzheimer patients. The results revealed that LVV measure has predictive performance in AD. We demonstrated that ALVIN and ImageJ are both effective in determining lateral ventricular volume, providing an objective tool for quantitative assessment of AD.     

Auditory post-processing in a passive listening task is deficient in Alzheimer’s disease

ObjectiveTo investigate whether automatic auditory post-processing is deficient in patients with Alzheimer’s disease and is related to sensory gating.MethodsEvent-related potentials were recorded during a passive listening task to examine the automatic transient storage of auditory information (short click pairs). Patients with Alzheimer’s disease were compared to a healthy age-matched control group. A young healthy control group was included to assess effects of physiological aging.ResultsA bilateral frontal negativity in combination with deep temporal positivity occurring 500 ms after stimulus offset was reduced in patients with Alzheimer’s disease, but was unaffected by physiological aging. Its amplitude correlated with short-term memory capacity, but was independent of sensory gating in healthy elderly controls. Source analysis revealed a dipole pair in the anterior temporal lobes.ConclusionResults suggest that auditory post-processing is deficient in Alzheimer’s disease, but is not typically related to sensory gating. The deficit could neither be explained by physiological aging nor by problems in earlier stages of auditory perception. Correlations with short-term memory capacity and executive control tasks suggested an association with memory encoding and/or overall cognitive control deficits.SignificanceAn auditory late negative wave could represent a marker of auditory working memory encoding deficits in Alzheimer’s disease.     

Presentation and stability of cognitive and noncognitive symptom patterns in patients with Alzheimer's disease. Disease course over a two-year period under constant treatment conditions with rivastigmine

The course of behavioural and psychotic features of patients with Alzheimer's disease treated with an inhibitor of the acetylcholinesterase (rivastigmine), and their association to cognitive impairment is presented in the study. Standardized examination of global functional deterioration (GDS), cognitive impairment (MMSE) and behavioural or psychotic symptoms (Behave-AD) were performed over two years. We could analyse the complete data from 44 of initially 91 patients with mild to moderate Alzheimer's disease. The cognitive component (measured by MMSE, ADAS-cog) and the functional assessment (GDS) showed a continuous decline after a one year period of stabilization, in contrast with behavioural and psychotic symptoms, especially delusions, which still improved after treatment of two years. While cognitive items in correlation with functional aspects formed a homogeneous factor over the two-year period, psychotic features displayed more variability over time evaluated by factor analysis. Nevertheless mood and anxiety disorder in combination with aggressive behaviour as well as hallucinations formed an independent factor in the course of Alzheimer's disease. In addition to other studies of the course of Alzheimer's disease we could demonstrate that distinct behavioural and psychotic symptoms may also present as independent factors in Alzheimer patients under constant treatment conditions with an inhibitor of the acetylcholinesterase (rivastigmine).     

Limb apraxia and verb processing in Alzheimer’s disease

Objective: The present research investigates language and praxis abilities in patients with Alzheimer’s disease in order to study the relationship between these two cognitive domains. Method: The experimental evaluation of patients and control group performance was designed to permit a direct comparison of linguistic abilities (i.e., verb and noun naming and sentence comprehension) and praxic abilities (i.e., gesture execution for complex movements). Moreover, for the first time, action comprehension was explored using the Action Sequence Comprehension. Results and conclusion: Analyses of variance (ANOVAs) and correlational analyses showed that a direct relationship may exist between language impairment and apraxia in patients with Alzheimer’s disease. In addition, the production and comprehension of both language and action were equally impaired in patients, providing further evidence for a spectrum of concomitant linguistic and praxis deficits in Alzheimer’s disease. Finally, the ability to correctly comprehend action semantics was related more directly to verb production ability than to noun production.