Altered spontaneous activity in Alzheimer's disease and mild cognitive impairment revealed by Regional Homogeneity

Alzheimer's disease (AD), the most prevalent cause of dementia in the elderly, is characterized by progressive cognitive and intellectual deficits. Most patients with mild cognitive impairment (MCI) are thought to be in a very early stage of AD. Resting-state functional magnetic resonance imaging reflects spontaneous brain activities and/or the endogenous/background neurophysiological process of the human brain. Regional Homogeneity (ReHo) can provide a fast method for mapping regional activity across the whole brain. Little has been previously published about where or how spontaneous activity differs between MCI and AD, although many previous fMRI studies have shown that the activity pattern is altered in MCI/AD. In the present study, we first used the ReHo method to explore differences in regional spontaneous activities throughout the whole brain between normal controls (NC) and people with MCI and with AD. A one-way ANOVA was performed to determine the regions in which the ReHo differs between the three groups, and then a post hoc analysis was performed to evaluate differences in the pattern among the three groups. Finally a correlation analysis was done between the ReHo index of these regions and clinical variables in order to evaluate the relationship between ReHo and cognitive measures in the AD and MCI groups. An exploratory classification analysis also demonstrated that ReHo measures were able to correctly separate subjects in 71.4% of the cases. Altered brain spontaneous activations were found in the medial prefrontal cortex, the bilateral posterior cingulate gyrus/precuneus and the left inferior parietal lobule (IPL) in both MCI and AD. In MCI, the ReHo index in the left IPL was higher than that of the NC, which could indicate the presence of a compensatory mechanism in MCI. More obviously, the correlation analysis indicated that the lower the memory and other cognitive abilities, the lower the ReHo in patients with MCI and AD. Combining our findings with the results in earlier studies, we propose that the spontaneous activity pattern in the resting state could potentially be used as a clinical marker for MCI/AD.     

Donepezil effects on sources of cortical rhythms in mild Alzheimer's disease: Responders vs. Non-Responders

Acetylcholinesterase inhibitors (AChEI) such as donepezil act in mild Alzheimer's disease (AD) by increasing cholinergic tone. Differences in the clinical response in patients who do or do not benefit from therapy may be due to different functional features of the central neural systems. We tested this hypothesis using cortical electroencephalographic (EEG) rhythmicity. Resting eyes-closed EEG data were recorded in 58 mild AD patients (Mini Mental State Examination [MMSE] range 17-24) before and approximately 1 year after standard donepezil treatment. Based on changes of MMSE scores between baseline and follow-up, 28 patients were classified as "Responders" (MMSEvar >or=0) and 30 patients as "Non-Responders" (MMSEvar <0). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). Cortical EEG sources were studied with low-resolution brain electromagnetic tomography (LORETA). Before treatment, posterior sources of delta, alpha 1 and alpha 2 frequencies were greater in amplitude in Non-Responders. After treatment, a lesser magnitude reduction of occipital and temporal alpha 1 sources characterized Responders. These results suggest that Responders and Non-Responders had different EEG cortical rhythms. Donepezil could act by reactivating existing yet functionally silent cortical synapses in Responders, restoring temporal and occipital alpha rhythms.     

老年性痴呆患者鞘内IgG合成率测定及意义

目的探讨老年性痴呆（ＡＤ）患者鞘内ＩｇＧ合成率与临床的关系。方法采用火箭电泳法（ＲＩＥ）检测ＡＤ患者和正常对照老年人 ６３例配对脑脊液和血清中 ＩｇＧ、白蛋白水平。并计算出每 ２４ ｈ鞘内 ＩｇＧ合成率。结果血清、脑脊液中白蛋白水平和 ＩｇＧ水平在三组间存在较大的重叠,无显著性差异;老年人 ２４ ｈ ＩｇＧ鞘内合成率增高较多,而且以多梗死性痴呆组升高最为显著。结论脑梗死时中枢神经系统存在异常免疫应答,但与 ＡＤ组相比无显著性差异。脑脊液 ２４ ｈ ＩｇＧ鞘内合成率增高可能反映老年人血脑通透性存在损伤,但难以确定与痴呆的关系。     

住院Alzheimer病精神症状分析

目的：为了解Ａｌｚｈｅｉｍｅｒ（ＡＤ）的精神症状及其相关因素。方法：用自编的调查表对所有住院的ＡＤ病人及其精神症状作详细调查, 并对各种精神症状进行分析讨论。结果： ８９．６６％ 的ＡＤ病人有精神症状, 其中幻觉为２３．０８％ ,妄想为５７．６９％ ,情感障碍为３４．６２％ ,行为障碍为９２．３１％ ,年龄组越高,妄想和行为障碍多见,文化程度高、痴呆程度轻者幻觉发生率高,疗程短者抑郁多见。结论：ＡＤ病人的精神症状较为常见,且与年龄、文化程度、病程、痴呆程度等有关。     

轻度阿尔茨海默病患者视网膜形态改变的观察

目的:通过观察轻度阿尔茨海默病(AD)患者的视神经纤维层厚度来评估视网膜形态改变。方法:比较15例轻度AD患者和15例对照组视网膜的形态差异。通过光学相干断层成像(OCT)测定视网膜上方、下方、鼻侧和颞侧的视神经纤维层的厚度,比较两组的差异。结果:AD患者的视神经纤维层的厚度与对照组相比,在各象限的数值和均值均显著减少(P<0.01)。结论:在轻度AD患者中视神经纤维层的厚度的减少提示在疾病早期即存在视网膜形态改变,OCT可能作为辅助手段有助诊断。     

Altered kallikrein 7 and 10 concentrations in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia

BACKGROUND: The role of various proteases in the pathogenesis of Alzheimer's disease is well documented. Recently, many members of the human tissue kallikrein family, a group of 15 secreted serine proteases, were found to be highly expressed in the central nervous system (CNS). Some of these enzymes can be measured in cerebrospinal fluid (CSF) by using ELISA-type methodologies. METHODS: We quantified various kallikreins in CSF of 20 patients with Alzheimer's disease (AD), 16 patients with frontotemporal dementia (FTD), and 15 controls. We then correlated the levels of various kallikreins with presence of AD or FTD. Among all kallikreins measured, detectable levels in CSF were identified for kallikreins hK6, hK7, and hK10. Other tested kallikreins (hK5, hK8, hK11, and hK13) were unmeasurable. The most notable differences between kallikrein levels in CSF and the three groups of subjects were seen between controls and FTD patients for hK6 (decrease in FTD; P = 0.017), controls and FTD patients for hK7 (decrease in FTD; P < 0.001), and controls and AD patients for hK7 (decrease in AD; P = 0.019). In addition, significant differences were seen between FTD patients or control subjects and patients with AD patients for hK10 (increase in AD; P < 0.02). Approximately half of the AD patients had CSF hK10 levels that were higher than all patients with FTD except one and all control subjects except two. Various kallikrein concentrations in CSF were correlated, the strongest correlation seen between hK6 and hK7 (r(s) = 0.58). We also observed a statistically significant association between decreasing hK7 concentration in CSF and possession of one or two ApoE4 alleles (P = 0.014). CONCLUSIONS: We demonstrate for the first time significant alterations of hK6, hK7, and hK10 concentration in CSF of patients with AD and FTD. Notably, all three kallikreins (hK6, hK7, and hK10) are decreased in CSF of FTD patients and hK10 is increased in CSF of AD patients, in comparison to control subjects. The possible connection between these enzymes and the pathogenesis and progression of AD and FTD needs to be further investigated.     

Neuropsychological correlates of amyloid precursor protein in Alzheimer's disease

The comprehensive cognitive screens for dementia, the Cambridge Cognitive screen (CAMCOG) and the Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE) were used for assessing use of the putative Alzheimer's disease biological marker, plasma amyloid precursor protein (APP), in Alzheimer's disease and Down syndrome. The analysis suggested that there were significant correlations between amyloid precursor protein and cognitive decline as assessed by the IQCODE. Preliminary investigations of Down syndrome suggest amyloid precursor protein levels are associated with duration of dementia in the group. The findings imply circulating amyloid precursor protein has a more central role in the pathogenesis of Alzheimer's disease.     

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.     

Current and future therapy in Alzheimer's disease

Dementia is increasingly being recognized as one of the most important medical problems in the elderly. As most pharmacological research within the field of dementia is focused on Alzheimer's dementia (AD), this review will focus on pharmacological interventions in AD. Most disease-modifying therapies are based on the amyloid hypothesis. In this hypothesis, the pathological accumulation of Aβ in the brain leads to oxidative stress, neuronal destruction and finally the clinical syndrome of AD. Following this hypothesis, secondary prevention of AD can be made by: decreasing the production of Aβ, stimulation of clearance of Aβ formed or prevention of aggregation of Aβ into amyloid plaques. First a short overview on current approved therapies for AD is given. The main part of the review will focus on potential disease-modifying therapies for AD that are currently being studied in phase I to phase III trials.     

阿尔茨海默病的PET分子影像学研究进展

阿尔茨海默病（AD）是一种好发于老年人的神经退行性疾病,是痴呆最常见的原因,发病隐匿且临床表现缺乏特异性,早期诊断困难。目前,基于生物标志物的AT（N）诊断框架使AD诊断的准确性明显提高。随着学科交叉融合的广泛推进,分子影像学展现出巨大潜力,是未来医学影像发展的趋势。PET显像可以在细胞和分子水平对活体内AD的病理过程进行定位和定量,是诊断AD重要的影像学手段,针对AD葡萄糖代谢和病理机制的多种示踪剂的研发有助于更好地研究AD的发病本质。本综述将对以淀粉样蛋白、Tau蛋白、葡萄糖、神经炎症、突触密度、神经递质为靶标的PET显像在AD诊断中的研究进展进行归纳阐述。     

阿尔茨海默症功能脑网络研究进展

近年来功能磁共振成像作为一种新兴的技术,被广泛应用于功能脑网络的研究中,一些功能脑网络被定义,如感觉运动网络、语言网络、默认模式网络、背侧注意网络、额顶叶控制网络、突显网络、中央执行网络等。阿尔茨海默症作为一种严重的神经退行性疾病,一直是脑科学中的研究热点,功能脑网络的研究为揭示其发病机制及早期诊断提供了可靠的依据。本文对功能脑网络用于阿尔茨海默症的研究进展进行综述。     

老年痴呆症患者的健康教育需求及对策

目的 了解老年痴呆患者健康教育需求并探讨相关对策.方法 采用自行设计的调查表,对50例老年痴呆患者的健康教育需求进行调查.结果 96%的患者能够明确疾病的诊断,但缺乏护理知识及技能;90%患者及家属希望医护人员示范讲解,面对面交谈健康教育知识;70.1%患者选择的教育方式为家访.结论 对老年痴呆症患者的健康教育刻不容缓.     

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.     

奥氮平联合吡拉西坦治疗阿尔茨海默病患者的效果

目的分析奥氮平联合吡拉西坦治疗阿尔茨海默病患者的效果。方法选取我院2017年10月至2019年8月收治的81例阿尔茨海默病患者作为研究对象,依照随机数字表法将其分为对照组(40例)和观察组(41例)。对照组接受奥氮平治疗,观察组接受奥氮平联合吡拉西坦治疗。比较两组临床疗效,治疗前及治疗1、3个月后阿尔茨海默病评定量表-认知量表(ADAS-cog)、阿尔茨海默病行为病理评定量表(BEHAVE-AD)、简易智能精神状态检查量表(MMSE)评分,治疗前、后血清白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)、巨噬细胞炎性蛋白-1α(MIP-1α)、单核细胞趋化蛋白-1(MCP-1)水平,不良反应发生情况。结果观察组的治疗总有效率明显高于对照组(P<0.05)。治疗1、3个月后,观察组的ADAS-cog、BEHAVE-AD评分低于对照组,MMSE评分高于对照组(P<0.05)。治疗后,两组血清IL-1β、TNF-α、MIP-1α、MCP-1水平均降低,且观察组低于对照组(P<0.05)。两组各不良反应发生率比较,差异无统计学意义(P>0.05)。结论奥氮平联合吡拉西坦治疗阿尔茨海默病患者效果显著,能有效改善患者认知、病理行为、智力水平,降低血清细胞因子水平,且安全性好。     

Alzheimer's disease: the pharmacological pathway

The current pharmacological treatment of Alzheimer's disease (AD) comes down to four marketed drugs (tacrine, donepezil, rivastigmine and galantamine) all of which are cholinesterase inhibitors, conforming to the cholinergic hypothesis. The future is clearly directed at new biological targets closely linked to the pathophysiology of the disease and more precisely, the pathological hallmark of AD which includes widespread neuronal degeneration, neuritic plaques containing beta-amyloid and tau-rich neurofibrillary tangles. For clinicians, this means that new curative drugs will have to be prescribed early in the course of the disease. This review describes the main entry pathways for drug discovery in AD: (1) supplementation therapy, (2) anti-apoptotic compounds, (3) substances with a mitochondrial impact, (4) anti-amyloid substances, (5) anti-protein aggregation and (6) lipid-lowering drugs. The rapidity at which these compounds will be at our disposal is highly dependent on the policy of the pharmaceutical companies.     

Neurotherapeutic applications of nanoparticles in Alzheimer's disease

A rapid increase in incidence of neurodegenerative disorders has been observed with the aging of the population. Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly. It is characterized by memory dysfunction, loss of lexical access, spatial and temporal disorientation and impairment of judgement clinically. Unfortunately, clinical development of drugs for the symptomatic and disease-modifying treatment of AD has resulted in both promise and disappointment. Indeed, a large number of drugs with differing targets and mechanisms of action were investigated with only a few of them being clinically available. The targeted drug delivery to the central nervous system (CNS), for the diagnosis and treatment of neurodegenerative disorders such as AD, is restricted due to the limitations posed by the blood-brain barrier (BBB) as well as due to opsonization by plasma proteins in the systemic circulation and peripheral side-effects. Over the last decade, nanoparticle-mediated drug delivery represents one promising strategy to successfully increase the CNS penetration of several therapeutic moieties. Different nanocarriers are being investigated to treat and diagnose AD by delivering at a constant rate a host of therapeutics over times extending up to days, weeks or even months. This review provides a concise incursion on the current pharmacotherapies for AD besides reviewing and discussing the literature on the different drug molecules that have been successfully encapsulated in nanoparticles (NPs). Some of them have been shown to cross the BBB and have been tested either for diagnosis or treatment of AD. Finally, the route of NPs administration and the future prospects will be discussed.     

Alzheimer's disease: Seeing the signs early

Purpose: Many patients with early symptoms of Alzheimer's disease (AD) first seek help from their primary care providers (PCPs). PCPs must therefore be watchful for signs and symptoms of AD, and should screen elderly patients who complain of memory and cognitive problems for dementia.
Data sources: Published literature on case detection, diagnosis, and treatment of AD.
Conclusions: There are a number of simple, accurate, and fast tools to facilitate case detection, including the Mini-Mental State Examination. Once a diagnosis has been made, healthcare providers, patients, and caregivers can evaluate treatment options. Several medications are available for symptomatic treatment of AD, including the cholinesterase inhibitors donepezil, galantamine, and rivastigmine, and for later stage disease, the N-methyl D-aspartate (NMDA) receptor antagonist, memantine.
Implications for Practice: Early intervention is critical because a delay in treatment is associated with nonreversible symptom progression. Realistic treatment expectations include reduction in symptom severity and slowed decline in cognition, function, and behavior. Treatment may allow patients to retain independence longer and reduce the burden that advanced AD places on caregivers.     

Diagnosing and treating Alzheimer's disease: a practitioner's overview

PURPOSE: To provide an overview of current diagnostic protocols of Alzheimer's disease (AD), screening techniques, tests, and a review of standard and new treatments. DATA SOURCES: Selected articles from the scientific literature, online sources, and standard texts were examined. CONCLUSIONS: Standard tools, such as the Geriatric Depression Scale, the Mini Mental State Evaluation, and the 7-Minute Screen, are useful in the primary care setting for screening elderly patients. Other tools, such as the Clinical Dementia Rating (CDR) and the Global Deterioration Scale, are useful for staging and monitoring progression of disease and response to treatment. Clinical diagnostic testing is still in developmental stages, but the hope is to have a reliable and objective diagnostic tool in order to diagnose AD in the earliest stages. IMPLICATIONS FOR PRACTICE: The diagnosis and treatment of AD is becoming a more frequent challenge in the primary care office. Clinicians must keep abreast of the rapid changes in new technologies in order to make informed diagnostic and therapeutic decisions.     

三磷酸腺苷结合盒转运蛋白7在阿尔茨海默病患者血清中表达及其与疾病预后的关系

目的探讨三磷酸腺苷结合盒转运蛋白7(ABCA7)在阿尔茨海默病(AD)患者血清中表达及其与疾病预后的关系。方法选取我院收治的126例AD患者纳入研究组,同期在我院进行体检的健康者53例纳入对照组,比较两组ABCA7水平,分析ABCA7在AD中的诊断价值。并给予多奈哌齐治疗研究组患者,根据患者预后情况分组,比较不同预后患者血清ABCA7水平,分析ABCA7与AD预后的相关性。结果研究组血清ABCA7水平低于对照组(P<0.05);以文献诊断结果为诊断金标准,血清ABCA7对AD的诊断准确率为85.71%,灵敏度为78.36%,特异性为71.21%;Logistic回归分析发现,Hcy≤13.9μmol/L、血清ABCA7<0.11μg、HDL是导致AD患者预后不佳的危险因素(P<0.05)。结论AD患者血清ABCA7显著高于健康人群,还可作为AD的临床诊断、评估治疗效果的有效指标。     

Atlas-based hippocampus segmentation in Alzheimer's disease and mild cognitive impairment

This study assesses the performance of public-domain automated methodologies for MRI-based segmentation of the hippocampus in elderly subjects with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Structural MR images of 54 age- and gender-matched healthy elderly individuals, subjects with probable AD, and subjects with MCI were collected at the University of Pittsburgh Alzheimer's Disease Research Center. Hippocampi in subject images were automatically segmented by using AIR, SPM, FLIRT, and the fully deformable method of Chen to align the images to the Harvard atlas, MNI atlas, and randomly selected, manually labeled subject images ("cohort atlases"). Mixed-effects statistical models analyzed the effects of side of the brain, disease state, registration method, choice of atlas, and manual tracing protocol on the spatial overlap between automated segmentations and expert manual segmentations. Registration methods that produced higher degrees of geometric deformation produced automated segmentations with higher agreement with manual segmentations. Side of the brain, presence of AD, choice of reference image, and manual tracing protocol were also significant factors contributing to automated segmentation performance. Fully automated techniques can be competitive with human raters on this difficult segmentation task, but a rigorous statistical analysis shows that a variety of methodological factors must be carefully considered to insure that automated methods perform well in practice. The use of fully deformable registration methods, cohort atlases, and user-defined manual tracings are recommended for highest performance in fully automated hippocampus segmentation.