A Metabolic Basis for Alzheimer Disease

Most studies of Alzheimer's disease (AD) have focused on a single precipitating alteration as the etiological event rather than global changes closely linked to aging. Recent evidence suggests that the most significant of these global changes are metabolic. Here we present data indicating that metabolic rate, nutrition, and neuronal size are all early indicators of AD. Understanding the cellular and molecular basis for these changes may open a new dimension to understanding AD.     

氧化应激与阿尔茨海默病

阿尔茨海默病(Alzheimer disease,AD)是一种多病因神经退行性疾病,以β-淀粉样蛋白(Aβ)聚集沉积引起的老年斑(senile plaque,SP),聚集的磷酸化微管稳定蛋白质(tau)引起的细胞内神经原纤维缠结(neurofibrillary tangle,NFT)为主要病理特征。活性氧(ROS)和活性氮(RNS)的增加引起的氧化应激和抗氧化防御酶功能丧失在AD形成中具有重要作用。综述近年来这方面的研究进展,着重总结了AD中的生物大分子(脂质、蛋白质和核酸)氧化以及Aβ和金属离子(铁、铜和锌等)动态平衡紊乱诱导的氧化应激与AD的关系,同时介绍了AD中氧化应激相关的信号转导,旨在对今后这方面的研究及预防和治疗AD提供帮助。     

多肽脯氨酰顺反异构酶与阿尔茨海默病

多肽脯氨酰顺反异构酶(简称Pinl)可专一性地使蛋白质一定区段内磷酸化的丝／苏氨酸模体发生顺反异构,从而改变该蛋白质的构型和功能。阿尔茨海默病中发生特征性改变的蛋白质如微管相关蛋白tau、淀粉样前体蛋白(APP)等都含有丝／苏氨酸模体,它们的活性和功能均受Pinl的变构调节。     

Enrichment and Stratification for Predementia Alzheimer Disease Clinical Trials

The tau and amyloid pathobiological processes underlying Alzheimer disease (AD) progresses slowly over periods of decades before clinical manifestation as mild cognitive impairment (MCI), then more rapidly to dementia, and eventually to end-stage organ failure. The failure of clinical trials of candidate disease modifying therapies to slow disease progression in patients already diagnosed with early AD has led to increased interest in exploring the possibility of early intervention and prevention trials, targeting MCI and cognitively healthy (HC) populations. Here, we stratify MCI individuals based on cerebrospinal fluid (CSF) biomarkers and structural atrophy risk factors for the disease. We also stratify HC individuals into risk groups on the basis of CSF biomarkers for the two hallmark AD pathologies. Results show that the broad category of MCI can be decomposed into subsets of individuals with significantly different average regional atrophy rates. By thus selectively identifying individuals, combinations of these biomarkers and risk factors could enable significant reductions in sample size requirements for clinical trials of investigational AD-modifying therapies, and provide stratification mechanisms to more finely assess response to therapy. Power is sufficiently high that detecting efficacy in MCI cohorts should not be a limiting factor in AD therapeutics research. In contrast, we show that sample size estimates for clinical trials aimed at the preclinical stage of the disorder (HCs with evidence of AD pathology) are prohibitively large. Longer natural history studies are needed to inform design of trials aimed at the presymptomatic stage.     

Modeling Test and Treatment Strategies for Presymptomatic Alzheimer Disease

Objectives

In this study, we developed a model of presymptomatic treatment of Alzheimer disease (AD) after a screening diagnostic evaluation and explored the circumstances required for an AD prevention treatment to produce aggregate net population benefit.

Methods

Monte Carlo simulation methods were used to estimate outcomes in a simulated population derived from data on AD incidence and mortality. A wide variety of treatment parameters were explored. Net population benefit was estimated in aggregated QALYs. Sensitivity analyses were performed by individually varying the primary parameters.

Findings

In the base-case scenario, treatment effects were uniformly positive, and net benefits increased with increasing age at screening. A highly efficacious treatment (i.e. relative risk 0.6) modeled in the base-case is estimated to save 20 QALYs per 1000 patients screened and 221 QALYs per 1000 patients treated.

Conclusions

Highly efficacious presymptomatic screen and treat strategies for AD are likely to produce substantial aggregate population benefits that are likely greater than the benefits of aspirin in primary prevention of moderate risk cardiovascular disease (28 QALYS per 1000 patients treated), even in the context of an imperfect treatment delivery environment.     

载脂蛋白E与阿尔茨海默病的关系

阿尔茨海默病(Alzheimer disease,AD)是最常见的一种老年性痴呆症,临床上以进行性记忆丧失和认知功能障碍为特征。流行病学资料表明,载脂蛋白E(apolipoprotein E,ApoE)的基因多态性与AD密切相关。ApoE不但影响了AD的发生年龄与危险性,还与AD特征性病理改变神经原纤维缠结(neurofibrillary tangle,NFT)和老年斑(senile plaque,SP)共定位。研究发现,ApoE可促进β-淀粉样肽(β—amyloid peptide,Aβ)的沉积和SP的形成,C末端切除的ApoE片段则促使Tau蛋白的过度磷酸化及NFT的形成,并进一步引起神经变性和行为缺陷。同时,ApoE还与炎症因子的表达相关。上述证据均提示了ApoE及其基因多态性在AD发病机制中的重要作用。     

载脂蛋白E基因多态性与阿尔茨海默病

利用PCR RFLP方法分析了中国汉族人群中 16 0例散发性阿尔茨海默病 (Alzheimerdisease,AD)患者和 195例正常对照老年人中载脂蛋白E(APOE)基因多态性分布的差异。结果表明 ,APOE 3种等位基因ε2、ε3和ε4的频率在AD组和对照组分别为 0 0 5 6、0 713、0 2 31和 0 0 82、0 84 4、0 0 74。APOEε4等位基因携带个体患AD的危险为非携带个体的 3 82倍 (χ2 =2 8 7,P <0 0 0 1)。 6 5岁以上APOEε4携带个体患AD的危险为非携带个体的 5 38倍(χ2 =2 9 8,P <0 0 0 1) ,说明年龄因素可能影响ε4与AD间的相互作用。APOE等位基因和基因型频率在轻、中和重度痴呆病人间的分布无明显差异 (P >0 0 5 ) ,提示APOE基因多态性可能与AD患者的痴呆程度无关联。APOEε4基因型频率在女性AD病人中的分布略高于男性AD病人 (4 3 0 %对 36 5 % ) ,女性ε4携带个体患AD的危险也高于男性ε4携带个体 (4 3倍对 3 3倍 ) ,但统计学分析未检测到这些差异的显著性 (P >0 0 5 )。ε2等位基因频率在AD患者男性亚组明显低于女性亚组 ,也低于对照人群的男性亚组 (P <0 0 5 ) ,提示ε2等位基因可能降低中国汉族男性人群AD发病的危险     

Phosphoprotein Phosphatase Activities in Alzheimer Disease Brain

Abstract: Microtubule-associated protein τ is known to be hyperphosphorylated in Alzheimer disease brain and this abnormal hyperphosphorylation is associated with an inability of τ to promote the assembly of microtubule in the affected neurons. Our previous studies demonstrated that abnormally phosphorylated τ could be dephosphorylated after treatment with alkaline phosphatase, thereby suggesting that the abnormal phosphorylation of τ might in part be the result of a deficiency of the phosphoprotein phosphatase system in patients with Alzheimer disease. In the present study we used ³²P-labeled phosphorylase kinase and poly(Glu.Tyr) 4:1 as substrates to measure phosphoprotein phosphatase activities in Alzheimer disease and control brains. The activities of phosphoseryl/ phosphothreonyl-protein phosphatase types 1, 2A, 2B, and 2C and of phosphotyrosyl-protein phosphatase in frontal gray and white matters from 13 Alzheimer brains were determined and compared with those from 12 age-matched control brains. The activities of type 1 phosphatase and phosphotyrosyl phosphatase in gray matter and of type 2A phosphatase in both gray and white matters were significantly lower in Alzheimer disease brains than in controls. These findings suggest that the hyperphosphorylation of τ in Alzheimer disease brain could result from a protein dephosphorylation defect in vivo. The decrease in the phosphatase activities in Alzheimer disease might also be involved in the formation of β-amyloid by augmenting the amyloidogenic pathway processing of β-amyloid precursor protein.     

The Senescence Hypothesis of Disease Progression in Alzheimer Disease: an Integrated Matrix of Disease Pathways for FAD and SAD

Alzheimer disease (AD) is a progressive, neurodegenerative disease characterised in life by cognitive decline and behavioural symptoms and post-mortem by the neuropathological hallmarks including the microtubule-associated protein tau-reactive tangles and neuritic plaques and amyloid-beta-protein-reactive senile plaques. Greater than 95 % of AD cases are sporadic (SAD) with a late onset and <5 % of AD cases are familial (FAD) with an early onset. FAD is associated with various genetic mutations in the amyloid precursor protein (APP) and the presenilins (PS)1 and PS2. As yet, no disease pathway has been fully accepted and there are no treatments that prevent, stop or reverse the cognitive decline associated with AD. Here, we review and integrate available environmental and genetic evidence associated with all forms of AD. We present the senescence hypothesis of AD progression, suggesting that factors associated with AD can be seen as partial stressors within the matrix of signalling pathways that underlie cell survival and function. Senescence pathways are triggered when stressors exceed the cells ability to compensate for them. The APP proteolytic system has many interactions with pathways involved in programmed senescence and APP proteolysis can both respond to and be driven by senescence-associated signalling. Disease pathways associated with sporadic disease may be different to those involving familial genetic mutations. The interpretation we provide strongly points to senescence as an additional underlying causal process in dementia progression in both SAD and FAD via multiple disease pathways.     

Increased Autophagic Degradation of Mitochondria in Alzheimer Disease

Extensive literature exists supporting a role for mitochondrial dysfunction and oxidative damage in the pathogenesis of Alzheimer disease. Mitochondria are a major source of intracellular reactive oxygen species and are particularly vulnerable to oxidative stress. It has been recently shown that the immunoreactivity of lipoic acid and cytochrome oxidase-1, two mitochondrial markers, is increased in the cytoplasm of pyramidal neurons in Alzheimer disease cases compared with controls. Furthermore, lipoic acid was found to be strongly associated with granular structures and, by ultrastructure analysis, it was shown to be localized in mitochondria, cytosol and, importantly, in organelles identified as autophagic vacuoles. Lipoic acid was also found associated with the electron dense core of lipofuscin in the brains of Alzheimer disease cases but not in controls, whereas cytochrome oxidase-1 immunoreactivity was limited to mitochondria and cytosol in both Alzheimer and control cases. These data suggest that mitochondria are key targets of increased autophagic degradation in Alzheimer disease. The study of autophagy in Alzheimer disease could clarify the mechanisms underlying this neurodegenerative disorder and, eventually, help in the development of new therapeutic strategies.

Addendum to:

Autophagocytosis of Mitochondria is Prominent in Alzheimer Disease

Moreira PI, Siedlak SL, Wang X, Santos MS, Oliveira CR, Tabaton M, Nunomura A, Szweda LI, Aliev G, Smith MA, Zhu X and Perry G

J Neuropathol Exp Neurol 2007; 66:525-32     

Characterization of Oral Disintegrating Film Containing Donepezil for Alzheimer Disease

The aim of this study was to develop a taste-masked oral disintegrating film (ODF) containing donepezil, with fast disintegration time and suitable mechanical strength, for the treatment of Alzheimer’s disease. Hydroxypropyl methylcellulose, corn starch, polyethylene glycol, lactose monohydrate and crosspovidone served as the hydrophilic polymeric bases of the ODF. The uniformity, in vitro disintegration time, drug release and the folding endurance of the ODF were examined. The in vitro results showed that 80% of donepezil hydrochloride was released within 5 minutes with mean disintegration time of 44 seconds. The result of the film flexibility test showed that the number of folding time to crack the film was 40 times, an indication of sufficient mechanical property for patient use. A single-dose, fasting, four-period, eight-treatment, double-blind study involving 16 healthy adult volunteers was performed to evaluate the in situ disintegration time and palatability of ODF. Five parameters, namely taste, aftertaste, mouthfeel, ease of handling and acceptance were evaluated. The mean in situ disintegration time of ODF was 49 seconds. ODF containing 7 mg of sucralose were more superior than saccharin and aspartame in terms of taste, aftertaste, mouthfeel and acceptance. Furthermore, the ODF was stable for at least 6 months when stored at 40°C and 75% relative humidity.     

热休克蛋白在阿尔茨海默病中的研究

热休克蛋白（heat shock protein,HSP）是一种重要的分子伴侣,它们参与辅助蛋白质合成、折叠、转运以及定位等过程,并且在协调蛋白质水解、阻止蛋白质错误折叠和聚积方面发挥重要作用。阿尔茨海默病（Alzheimer＇s disease,AD）是最常见的神经退行性疾病,以神经细胞内过度磷酸化的tau蛋白异常聚积形成神经原纤维缠结以及细胞外β淀粉样蛋白（β-amyloid,Aβ）异常折叠形成淀粉样斑为主要病理特征。研究表明HSP不但对tau蛋白的聚积／降解发挥重要作用,并且可抑制Aβ相关的毒性作用。这些研究结果提示了分子伴侣有可能成为AD治疗的新靶点,现对该方面的研究进展进行综述。     

Representative Claims in Healthcare: Identifying the Variety in Patient Representation

In many countries patient involvement is high on the healthcare policy agenda, which includes patient representation in collective decision-making. Patient organizations are generally considered to be important representatives of patients. Other actors also claim to represent patients in decision-making, such as politicians, healthcare professionals, and client advisory councils. In this paper we take a broad view of patient representation, examining all the actors claiming to represent patients in the Dutch debate on the decentralization of care. We conclude that variety in forms of representation could help do justice to the variety of patient preferences. In addition we conclude that in order to ensure the democratic quality of patient representation, actors making representative claims have to reflect on how their claims relate to each other and how they can ensure authorization and accountability in the representative relationship with those they claim to represent.     

Rates of Decline in Alzheimer Disease Decrease with Age

Age is the strongest risk factor for sporadic Alzheimer disease (AD), yet the effects of age on rates of clinical decline and brain atrophy in AD have been largely unexplored. Here, we examined longitudinal rates of change as a function of baseline age for measures of clinical decline and structural MRI-based regional brain atrophy, in cohorts of AD, mild cognitive impairment (MCI), and cognitively healthy (HC) individuals aged 65 to 90 years (total n = 723). The effect of age was modeled using mixed effects linear regression. There was pronounced reduction in rates of clinical decline and atrophy with age for AD and MCI individuals, whereas HCs showed increased rates of clinical decline and atrophy with age. This resulted in convergence in rates of change for HCs and patients with advancing age for several measures. Baseline cerebrospinal fluid densities of AD-relevant proteins, Aβ_1–42, tau, and phospho-tau_181p (ptau), showed a similar pattern of convergence with advanced age across cohorts, particularly for ptau. In contrast, baseline clinical measures did not differ by age, indicating uniformity of clinical severity at baseline. These results imply that the phenotypic expression of AD is relatively mild in individuals older than approximately 85 years, and this may affect the ability to distinguish AD from normal aging in the very old. Our findings show that inclusion of older individuals in clinical trials will substantially reduce the power to detect disease-modifying therapeutic effects, leading to dramatic increases in required clinical trial sample sizes with age of study sample.     

Examination of Candidate Exonic Variants for Association to Alzheimer Disease in the Amish

Alzheimer disease (AD) is the most common cause of dementia. As with many complex diseases, the identified variants do not explain the total expected genetic risk that is based on heritability estimates for AD. Isolated founder populations, such as the Amish, are advantageous for genetic studies as they overcome heterogeneity limitations associated with complex population studies. We determined that Amish AD cases harbored a significantly higher burden of the known risk alleles compared to Amish cognitively normal controls, but a significantly lower burden when compared to cases from a dataset of unrelated individuals. Whole-exome sequencing of a selected subset of the overall study population was used as a screening tool to identify variants located in the regions of the genome that are most likely to contribute risk. By then genotyping the top candidate variants from the known AD genes and from linkage regions implicated previous studies in the full dataset, new associations could be confirmed. The most significant result (p = 0.0012) was for rs73938538, a synonymous variant in LAMA1 within the previously identified linkage peak on chromosome 18. However, this association is specific to the Amish and did not generalize when tested in a dataset of unrelated individuals. These results suggest that additional risk variation in the Amish remains to be identified and likely resides outside of the classical protein coding gene regions.