阿司匹林在阿尔茨海默病防治中作用机制研究进展

阿尔茨海默病(Alzheimer′s disease,AD)主要临床表现为进行性记忆力减退、认知功能障碍以及人格改变等症状,其主要病理改变是:大脑皮层及海马区的β淀粉样蛋白(amyloidβ-peptide,Aβ)在胞外积累并形成老年斑(senile plaque,SP)、脑神经细胞内tau蛋白异常聚集形成的神经元纤维缠结(neurofibrillary tangle,NFT)、神经元突触功能异常及锥体神经细胞的丢失。     

阿尔茨海默病β-淀粉样蛋白清除相关基因的研究进展

阿尔茨海默病(Alzheimer's disease,AD)是一种以进行性认知功能减退包括记忆障碍和痴呆为特征的神经变性疾病,主要的病理特征包括神经细胞外以β-淀粉样蛋白(Aβ)沉积为核心形成的老年斑(senile plaque,SP),细胞内以超磷酸化的Tau蛋白为核心形成的神经原纤维缠结(neurofibrillary tangles,NFT)及神经细胞突触的丢失和脑萎缩.     

营养因素与阿尔茨海默病的相关性研究进展

正阿尔茨海默病(AD)是一种起病隐匿的进行性中枢神经系统退行性疾病。AD的主要病理改变为β-淀粉样蛋白(Aβ)在神经细胞外沉积形成的老年斑和过度磷酸化的tau蛋白在神经细胞内沉积形成的神经元纤维缠结~([1])。另外氧化应激、线粒体功能障碍、炎性蛋白毒性作用,以及基因表达的改变等也参与了AD     

阿尔茨海默病免疫治疗的药物临床试验进展

<正>β淀粉样蛋白(Aβ)沉积是老年痴呆最典型的病理特征之一。大量证据表明[1],Aβ沉积和疾病的发生发展具有很强的相关性,AD患者大脑区域的Aβ1-40和Aβ1-42含量几乎与其认知能力损伤具有定量的相关性。Aβ蛋白、Aβ分子寡聚体、Aβ斑块具有很强的神经毒性,可活化神经胶质细胞,诱导神经元的凋亡、神经突触形成不良等改变,最终引起一系列的病理改变[2-3]。因此,     

11C-PIB PET在阿尔茨海默病中的应用进展

阿尔茨海默病(AD)是一种进行性认知功能障碍为核心的中枢神经系统变性病[1],患者不仅存在脑组织结构和功能的异常,还有脑分子代谢改变.阿尔茨海默病生物标志物是评估疾病病理生理学特征的客观量化指标[2],近年来 NIA-AA[3]提出 AT (N)研究框架,其将生物标志物β-淀粉样蛋白(Aβ)沉积(A)、病理性tau蛋白...     

慢性应激中糖皮质激素及其受体在阿尔茨海默病中的作用

阿尔茨海默病(Alzheimer's disease,AD)的高患病率给家庭和社会带来沉重的负担。最近很多动物研究表明慢性应激导致的糖皮质激素(glucocorticoid,GC)水平增加及其受体功能异常参与AD的病理进程,其涉及的机制包括增加Aβ沉积与tau蛋白过度磷酸化、损害突触可塑性、与小胶质细胞共同介导慢性炎症等。给予糖皮质激素受体(glucocorticoidreceptor,GR)拮抗剂能够改善AD动物模型的认知表现。本文综述了GC及GR在AD病理中的可能作用机制,并为AD的研究和治疗提供新的思路与方法。     

Tau蛋白在阿尔茨海默病中的作用研究进展

阿尔茨海默病(AD)的典型病理特征是存在神经细胞外β淀粉样蛋白(Aβ)异常沉积形成的老年斑和神经细胞内磷酸化的微管相关蛋白Tau蛋白自聚集出现的神经纤维缠结(NFTs)两种异常结构。Aβ和Tau病理并不总是重叠。目前尽管Aβ和Tau已得到广泛研究,但由于AD是中枢神经系统退行性疾病,因此有人提出Aβ可能引发疾病过程,而Tau是执行者。本文集中讨论Tau病理学的研究进展。     

p38MAPK信号转导途径与阿尔茨海默病

阿尔茨海默病（Alzheimer disease，AD）是老年人常见的神经系统变性疾病，是痴呆最常见的病因。临床表现为进行性认知功能障碍和神经精神异常。老年斑（senile plaques，SP）和神经纤维缠结（neurofibrillary tangles，NFTs）是两个标志性病理改变。这两种损害是病理性蛋白沉积的结果——细胞外β淀粉样蛋白（β-amyloid，Aβ）沉积导致SP的形成；     

阿尔茨海默病的1H-MRS成像研究进展

阿尔茨海默病(Alzheimer's disease,AD)是一种最常见的老年期痴呆综合征,临床早期突出表现为陈述性记忆障碍,随着病情发展出现严重的智能衰退,特征性的病理改变是老年斑、神经原纤维缠结及选择性神经元和突触的缺失.     

运动调控PI3K/Akt信号通路改善阿尔茨海默病的研究进展

正阿尔茨海默病(Alzheimer's disease,AD)是一种多发于中老年时期的神经系统退行性疾病,主要病理表现为β-淀粉样蛋白(amyloidβ-protein,Aβ)沉积形成的老年斑(senile plaques,SP)、Tau蛋白过度磷酸化形成的神经元纤维缠结(neurofibrillary tangles,NFTs)以及神经元数量显著减少[1]。Aβ沉积、过度磷酸化的Tau,神经炎症和细胞过度凋亡,可损伤神经元,造成学习记忆障碍。随着全球老龄化人口的递增,AD发病率也急剧攀升,给家庭和社会带来了沉重负担,     

工作记忆与Alzheimer病工作记忆障碍的功能磁共振成像研究

工作记忆属于短时记忆的一种,在人类记忆过程中起重要作用.老年性痴呆(Alzheimer's disease,AD)是一种以记忆缺陷为主要临床表现的脑变性疾病.本文就功能磁共振成像在工作记忆及AD工作记忆缺陷方面的研究进展进行综述.     

Overexpression of the high affinity choline transporter in cortical regions affected by Alzheimer's disease. Evidence from rapid autopsy studies.

Cholinergic deficits in Alzheimer's disease are typically assessed by choline acetyltransferase, the enzyme that synthesizes acetylcholine. However, the determining step in acetylcholine formation is choline uptake via a high affinity transporter in nerve terminal membranes. Evaluating uptake is difficult because regulatory changes in transporter function decay rapidly postmortem. To overcome this problem, brain regions from patients with or without Alzheimer's disease were frozen within 4 h of death and examined for both choline acetyltransferase activity and for binding of [3H]-hemicholinium-3 to the choline transporter. Consistent with the loss of cholinergic projections, cerebral cortical areas exhibited marked decreases in enzyme activity whereas the putamen, a region not involved in Alzheimer's disease, was unaffected. However, [3H]hemicholinium-3 binding was significantly enhanced in the cortical regions. In the frontal cortex, the increase in [3H]hemicholinium-3 binding far exceeded the loss of choline acetyltransferase, indicating transporter overexpression beyond that necessary to offset loss of synaptic terminals. These results suggest that, in Alzheimer's disease, the loss of cholinergic function is not dictated simply by destruction of nerve terminals, but rather involves additional alterations in choline utilization; interventions aimed at increasing the activity of cholinergic neurons may thus accelerate neurodegeneration.     

Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

Learning and memory deficits are early clinical manifestations of Huntington’s disease (HD). These cognitive impairments have been mainly associated with frontostriatal HD pathology; however, compelling evidence provided by several HD murine models suggests that the hippocampus may contribute to synaptic deficits and memory dysfunction in HD. The neurotrophin receptor p75^NTR negatively regulates spine density, which is associated with learning and memory; therefore, we explored whether disturbed p75^NTR function in the hippocampus could contribute to synaptic dysfunction and memory deficits in HD. Here, we determined that levels of p75^NTR are markedly increased in the hippocampus of 2 distinct mouse models of HD and in HD patients. Normalization of p75^NTR levels in HD mutant mice heterozygous for p75^NTR prevented memory and synaptic plasticity deficits and ameliorated dendritic spine abnormalities, likely through normalization of the activity of the GTPase RhoA. Moreover, viral-mediated overexpression of p75^NTR in the hippocampus of WT mice reproduced HD learning and memory deficits, while knockdown of p75^NTR in the hippocampus of HD mice prevented cognitive decline. Together, these findings provide evidence of hippocampus-associated memory deficits in HD and demonstrate that p75^NTR mediates synaptic, learning, and memory dysfunction in HD.     

Basal functional connectivity within the anterior temporal network is associated with performance on declarative memory tasks

Spontaneous fluctuations in the blood oxygenation level-dependent (BOLD) signal, as measured by functional magnetic resonance imaging (fMRI) at rest, exhibit a temporally coherent activity thought to reflect functionally relevant networks. Antero-mesial temporal structures are the site of early pathological changes in Alzheimer's disease and have been shown to be critical for declarative memory. Our study aimed at exploring the functional impact of basal connectivity of an anterior temporal network (ATN) on declarative memory. A heterogeneous group of subjects with varying performance on tasks assessing memory was therefore selected, including healthy subjects and patients with isolated memory complaint, amnestic Mild Cognitive Impairment (aMCI) and mild Alzheimer's disease (AD). Using Independent Component Analysis on resting-state fMRI, we extracted a relevant anterior temporal network (ATN) composed of the perirhinal and entorhinal cortex, the hippocampal head, the amygdala and the lateral temporal cortex extending to the temporal pole. A default mode network and an executive-control network were also selected to serve as control networks. We first compared basal functional connectivity of the ATN between patients and control subjects. Relative to controls, patients exhibited significantly increased functional connectivity in the ATN during rest. Specifically, voxel-based analysis revealed an increase within the inferior and superior temporal gyrus and the uncus. In the patient group, positive correlations between averaged connectivity values of ATN and performance on anterograde and retrograde object-based memory tasks were observed, while no correlation was found with other evaluated cognitive measures. These correlations were specific to the ATN, as no correlation between performance on memory tasks and the other selected networks was found. Taken together, these findings provide evidence that basal connectivity inside the ATN network has a functional role in object-related, context-free memory. They also suggest that increased connectivity at rest within the ATN could reflect compensatory mechanisms that occur in response to early pathological insult.     

T1rho MRI of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Classic symptoms of the disease include memory loss and confusion associated with the hallmark neuro-pathologic lesions of neurofibrillary tangles (NFT) and senile plaques (SP) and their sequelae, gray matter atrophy. Volumetric assessment methods measure tissue atrophy, which typically follows early biochemical changes. An alternate MRI contrast mechanism to visualize the early pathological changes is T1rho (or "T-1-rho"), the spin lattice relaxation time constant in the rotating frame, which determines the decay of the transverse magnetization in the presence of a "spin-lock" radio-frequency field. Macromolecular changes (in plaques and tangles) that accompany early AD are expected to alter bulk water T1rho relaxation times. In this work, we measure T1rho MRI on patients with clinically diagnosed AD, MCI and in age-matched cognitively normal control subjects in order to compare T1rho values with changes in brain volume in the same regions of the brain and demonstrate that T1rho can potentially constitute an important biomarker of AD.     

Clinical relevance of the neurotrophins and their receptors

The neurotrophins are growth factors required by discrete neuronal cell types for survival and maintenance, with a broad range of activities in the central and peripheral nervous system in the developing and adult mammal. This review examines their role in diverse disease states, including Alzheimer's disease, depression, pain and asthma. In addition, the role of BDNF (brain-derived neurotrophic factor) in synaptic plasticity and memory formation is discussed. Unlike the other neurotrophins, BDNF is secreted in an activity-dependent manner that allows the highly controlled release required for synaptic regulation. Evidence is discussed which shows that sequestration of NGF (nerve growth factor) is able to reverse symptoms of inflammatory pain and asthma in animal models. Both pain and asthma show an underlying pathophysiology linked to increases in endogenous NGF and subsequent NGF-dependent increase in BDNF. Conversely, in Alzheimer's disease, there is a role for NGF in the treatment of the disease and a recent clinical trial has shown benefit from its exogenous application. In addition, reductions in BDNF, and changes in the processing and usage of NGF, are evident and it is possible that both NGF and BDNF play a part in the aetiology of the disease process. This highly selective choice of functions and disease states related to neurotrophin function, although in no way comprehensive, illustrates the importance of the neurotrophins in the brain, the peripheral nervous system and in non-neuronal tissues. Ways in which the neurotrophins, their receptors or agonists/antagonists may act therapeutically are discussed.     

Neural correlates of Alzheimer's disease and mild cognitive impairment: A systematic and quantitative meta-analysis involving 1351 patients

Alzheimer's disease is the most common form of dementia. Its prodromal stage amnestic mild cognitive impairment is characterized by deficits of anterograde episodic memory. The development of standardized imaging inclusion criteria has to be regarded as a prerequisite for future diagnostic systems. Moreover, successful treatment requires isolating imaging markers predicting the disease. Accordingly, we conducted a systematic and quantitative meta-analysis to reveal the prototypical neural correlates of Alzheimer's disease and its prodromal stage. To prevent any a priori assumptions and enable a data-driven approach only studies applying quantitative automated whole brain analysis were included. Finally, 40 studies were identified involving 1351 patients and 1097 healthy control subjects reporting either atrophy or decreases in glucose utilization and perfusion. The currently most sophisticated and best-validated of coordinate-based voxel-wise meta-analyses was applied (anatomical likelihood estimates). The meta-analysis reveals that early Alzheimer's disease affects structurally the (trans-)entorhinal and hippocampal regions, functionally the inferior parietal lobules and precuneus. Results further may suggest that atrophy in the (trans-)entorhinal area/hippocampus and hypometabolism/hypoperfusion in the inferior parietal lobules predicts most reliably the progression from amnestic mild cognitive impairment to Alzheimer's disease, whereas changes in the posterior cingulate cortex and precuneus are unspecific. Fully developed Alzheimer's disease involved additionally a frontomedian-thalamic network. In conclusion, the meta-analysis characterizes the prototypical neural substrates of Alzheimer's disease and its prodromal stage amnestic mild cognitive impairment. By isolating predictive markers it enables successful treatment strategies in the future and contributes to standardized imaging inclusion criteria for Alzheimer's disease as suggested for future diagnostic systems.     

Effects of T-588, a cognitive enhancer compound, on synaptic plasticity in the dentate gyrus of freely moving rats.

(1R)-1-benzo [b] thiophen-5-yl-2-[2-(diethylamino) ethoxy] ethan-1-ol hydrochloride (T-588) is a compound for the treatment of neurodegenerative disorders, including Alzheimer's disease and cerebrovascular diseases. T-588 reportedly alleviates learning and memory deficits in animal models of dementia. In the present study, we investigated the effects of T-588 on the induction and decay of long-term potentiation (LTP) and on the responses to paired-pulse (pp) stimulation in freely moving rats. Perforant path-evoked field potentials were recorded in the dentate gyrus by chronically implanted electrodes. LTP was induced by high-frequency stimulation 30 min after oral administration of T-588 (0.3 or 3 mg/kg). T-588 significantly augmented the increase in population spike amplitude and field excitatory postsynaptic potential slope after LTP induction. T-588 also prolonged the decay of augmented population spike amplitude, but had no significant effect on the response to pp stimulation. These results suggest that T-588 facilitates long-term synaptic plasticity, but not short-term synaptic plasticity in the dentate gyrus of freely moving rats. The effect of T-588 on long-term synaptic plasticity may contribute to the alleviation of learning and memory dysfunction seen in animal models.     

Neurodegenerative diseases

Neurodegenerative diseases are characterized by pathological changes, neuronal loss and gliosis. These disease involved changes of neurotransmitter in central nervous system. In Alzheimer's disease, cholinergic neurons were depleted. In Parkinson's disease(PD), while several kinds of mediator were affected, dopaminergic neurons were mainly associated with motor and non-motor symptoms. Antipsychotic drugs may induce worsening of parkinsonism and neuroleptic malignant syndrome in PD and dementia Lewy bodies(DLB). Therefore, it is recommended to use atypical antipsychotic drugs, especially quetiapine, for treatment of psychosis in PD and DLB.     

老年痴呆患者住院期间的风险管理

痴呆病人记忆力差,生活活动能力减退,且可出现行为错乱等情况,护理中潜在很大的风险,本文通过老年病人痴呆患者的观察要点为患者提供安全、有序、优良的护理服务,预防老年性痴呆的健康教育指导等方面来加强老年痴呆患者住院期间的风险管理.