Alzheimer's disease: rapid and slow progression

The variability in the progression of Alzheimer''s disease (AD) across patients has made identification of disease-delaying treatments difficult. Quantitative analysis of this variability has important implications in understanding the pathophysiology of AD and identifying disease-delaying treatments. The functional assessment staging (FAST) procedure characterizes seven stages in the course of AD from normal ageing to severe dementia. The present study applied statistical methods to analyse FAST stage durations from a dataset of 648 AD patients. These methods uncovered two distinct types of disease progression, characterized by different mean progression rates. We identified two separate distributions of FAST stage progression times differing by up to 2 years in mean duration within each stage. These results further indicate that if a patient progresses rapidly through a given FAST stage, then their further progression is also likely to be rapid. These findings support the hypothesis that progression of AD can occur via two different pathophysiological mechanisms that lead to distinct average rates of decline.     

Constructing and characterizing a bioactive small molecule and microRNA association network for Alzheimer's disease

Alzheimer''s disease (AD) is an incurable neurodegenerative disorder. Much effort has been devoted to developing effective therapeutic agents. Recently, targeting microRNAs (miRNAs) with small molecules has become a novel therapy for human diseases. In this study, we present a systematic computational approach to construct a bioactive Small molecule and miRNA association Network in AD (SmiRN-AD), which is based on the gene expression signatures of bioactive small molecule perturbation and AD-related miRNA regulation. We also performed topological and functional analysis of the SmiRN-AD from multiple perspectives. At the significance level of p ≤ 0.01, 496 small molecule–miRNA associations, including 25 AD-related miRNAs and 275 small molecules, were recognized and used to construct the SmiRN-AD. The drugs that were connected with the same miRNA tended to share common drug targets (p = 1.72 × 10⁻⁴) and belong to the same therapeutic category (p = 4.22 × 10⁻⁸). The miRNAs that were linked to the same small molecule regulated more common miRNA targets (p = 6.07 × 10⁻³). Further analysis of the positive connections (quinostatin and miR-148b, amantadine and miR-15a) and the negative connections (melatonin and miR-30e-5p) indicated that our large-scale predictions afforded specific biological insights into AD pathogenesis and therapy. This study proposes a holistic strategy for deciphering the associations between small molecules and miRNAs in AD, which may be helpful for developing a novel effective miRNA-associated therapeutic strategy for AD. A comprehensive database for the SmiRN-AD and the differential expression patterns of the miRNA targets in AD is freely available at http://bioinfo.hrbmu.edu.cn/SmiRN-AD/.     

Cerebrospinal fluid dynamics in the human cranial subarachnoid space: an overlooked mediator of cerebral disease. I. Computational model

Abnormal cerebrospinal fluid (CSF) flow is suspected to be a contributor to the pathogenesis of neurodegenerative diseases such as Alzheimer''s through the accumulation of toxic metabolites, and to the malfunction of intracranial pressure regulation, possibly through disruption of neuroendocrine communication. For the understanding of transport processes involved in either, knowledge of in vivo CSF dynamics is important. We present a three-dimensional, transient, subject-specific computational analysis of CSF flow in the human cranial subarachnoid space (SAS) based on in vivo magnetic resonance imaging. We observed large variations in the spatial distribution of flow velocities with a temporal peak of 5 cm s⁻¹ in the anterior SAS and less than 4 mm s⁻¹ in the superior part. This could reflect dissimilar flushing requirements of brain areas that may show differences in susceptibility to pathological CSF flow. Our methods can be used to compare the transport of metabolites and neuroendocrine substances in healthy and diseased brains.     

Nonlinear speech analysis algorithms mapped to a standard metric achieve clinically useful quantification of average Parkinson's disease symptom severity

The standard reference clinical score quantifying average Parkinson''s disease (PD) symptom severity is the Unified Parkinson''s Disease Rating Scale (UPDRS). At present, UPDRS is determined by the subjective clinical evaluation of the patient''s ability to adequately cope with a range of tasks. In this study, we extend recent findings that UPDRS can be objectively assessed to clinically useful accuracy using simple, self-administered speech tests, without requiring the patient''s physical presence in the clinic. We apply a wide range of known speech signal processing algorithms to a large database (approx. 6000 recordings from 42 PD patients, recruited to a six-month, multi-centre trial) and propose a number of novel, nonlinear signal processing algorithms which reveal pathological characteristics in PD more accurately than existing approaches. Robust feature selection algorithms select the optimal subset of these algorithms, which is fed into non-parametric regression and classification algorithms, mapping the signal processing algorithm outputs to UPDRS. We demonstrate rapid, accurate replication of the UPDRS assessment with clinically useful accuracy (about 2 UPDRS points difference from the clinicians'' estimates, p < 0.001). This study supports the viability of frequent, remote, cost-effective, objective, accurate UPDRS telemonitoring based on self-administered speech tests. This technology could facilitate large-scale clinical trials into novel PD treatments.     

Cerebrospinal fluid dynamics in the human cranial subarachnoid space: an overlooked mediator of cerebral disease. II. In vitro arachnoid outflow model

The arachnoid membrane (AM) and granulations (AGs) are important in cerebrospinal fluid (CSF) homeostasis, regulating intracranial pressure in health and disease. We offer a functional perspective of the human AM''s transport mechanism to clarify the role of AM in the movement of CSF and metabolites. Using cultures of human AG cells and a specialized perfusion system, we have shown that this in vitro model mimics the in vivo characteristics of unidirectional fluid transport and we present the first report of serum-free permeability values (92.5 µl min⁻¹ mm Hg⁻¹ cm⁻²), which in turn are in agreement with the CSF outflow rates derived from a dynamic, in vivo magnetic resonance imaging-based computational model of the subarachnoid cranial space (130.9 µl min⁻¹ mm Hg⁻¹ cm⁻²). Lucifer yellow permeability experiments have verified the maintenance of tight junctions by the arachnoidal cells with a peak occurring around 21 days post-seeding, which is when all perfusion experiments were conducted. Addition of ruthenium red to the perfusate, and subsequent analysis of its distribution post-perfusion, has verified the passage of perfusate via both paracellular and transcellular mechanisms with intracellular vacuoles of approximately 1 µm in diameter being the predominant transport mechanism. The comparison of the computational and in vitro models is the first report to measure human CSF dynamics functionally and structurally, enabling the development of innovative approaches to modify CSF outflow and will change concepts and management of neurodegenerative diseases resulting from CSF stagnation.     

Selection methods regulate evolution of cooperation in digital evolution

A key, yet often neglected, component of digital evolution and evolutionary models is the ‘selection method’ which assigns fitness (number of offspring) to individuals based on their performance scores (efficiency in performing tasks). Here, we study with formal analysis and numerical experiments the evolution of cooperation under the five most common selection methods (proportionate, rank, truncation-proportionate, truncation-uniform and tournament). We consider related individuals engaging in a Prisoner''s Dilemma game where individuals can either cooperate or defect. A cooperator pays a cost, whereas its partner receives a benefit, which affect their performance scores. These performance scores are translated into fitness by one of the five selection methods. We show that cooperation is positively associated with the relatedness between individuals under all selection methods. By contrast, the change in the performance benefit of cooperation affects the populations’ average level of cooperation only under the proportionate methods. We also demonstrate that the truncation and tournament methods may introduce negative frequency-dependence and lead to the evolution of polymorphic populations. Using the example of the evolution of cooperation, we show that the choice of selection method, though it is often marginalized, can considerably affect the evolutionary dynamics.     

Genomic mutation rates that neutralize adaptive evolution and natural selection

When mutation rates are low, natural selection remains effective, and increasing the mutation rate can give rise to an increase in adaptation rate. When mutation rates are high to begin with, however, increasing the mutation rate may have a detrimental effect because of the overwhelming presence of deleterious mutations. Indeed, if mutation rates are high enough: (i) adaptive evolution may be neutralized, resulting in a zero (or negative) adaptation rate despite the continued availability of adaptive and/or compensatory mutations, or (ii) natural selection may be neutralized, because the fitness of lineages bearing adaptive and/or compensatory mutations—whether established or newly arising—is eroded by excessive mutation, causing such lineages to decline in frequency. We apply these two criteria to a standard model of asexual adaptive evolution and derive mathematical expressions—some new, some old in new guise—delineating the mutation rates under which either adaptive evolution or natural selection is neutralized. The expressions are simple and require no a priori knowledge of organism- and/or environment-specific parameters. Our discussion connects these results to each other and to previous theory, showing convergence or equivalence of the different results in most cases.     

阿尔茨海默老年人卫生洁具产品创新设计研究

目的 本研究旨在设计并开发一款专为躺卧人群,特别是患有阿尔茨海默病等需长期卧床的老年群体量身定制的智能卫生洁具。方法 首先采用历史文献综述法,系统性地回顾并分析了古代“溺器”与现代卫生洁具之间的历史演变关系,特别聚焦于古代卫生洁具“虎子”的形制变迁及其背后的社会文化因素。随后,结合阿尔茨海默病患者的生理特征,如认知功能下降、行动不便等,深入剖析这些特征对卫生洁具设计提出的具体要求。将古代卫生洁具的设计智慧与现代人体工程学、产品设计理论相结合,提取出适用于现代躺卧人群使用的关键结构特点。在此基础上,构建了一套基于阿尔茨海默病患者如厕行为的需求层次模型,该模型涵盖了基本生理需求、发展需求以及与之紧密相关的物理环境（如洁具的尺寸、材质、易清洁性）和社会环境（如隐私保护、操作简便性）等多个维度的指标。结论 从传统工艺美术品中汲取灵感,创新性地提出了一种基于历史智慧与现代科技融合的仿真设计方法。通过该方法,我们不仅验证了所设计智能卫生洁具的可行性,还展示了其在提升躺卧人群生活质量方面的显著优势。本研究不仅为同类产品的创新设计提供了新的发展思路,也为未来智能家居、医疗辅助设备等领域的研究提供了有益的参考和借鉴。     

防治老年人阿尔茨海默症的情感关怀交互产品设计研究

目的 基于对老年阿尔茨海默症患者的调查与分析,提出运用情感关怀交互产品的设计思维和方法,设计针对老年阿尔茨海默症患者家庭陪护的情感关怀产品系统。方法 在进行文献调研和实地调研的基础上,结合交互设计在形式、内容、行为3个层次对情感交互的设计要求和侧重,进行产品设计的探讨。结论 提出了将音乐疗法与敲击游戏、脑力训练与日常就餐、专业指导与日常生活相结合的设计需求,并在实物产品和移动应用两个方面研究其情感交互的组成及创新。     

Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimer's disease peptide β-amyloid (1–42)

For decades, a link between increased levels of iron and areas of Alzheimer''s disease (AD) pathology has been recognized, including AD lesions comprised of the peptide β-amyloid (Aβ). Despite many observations of this association, the relationship between Aβ and iron is poorly understood. Using X-ray microspectroscopy, X-ray absorption spectroscopy, electron microscopy and spectrophotometric iron(II) quantification techniques, we examine the interaction between Aβ(1–42) and synthetic iron(III), reminiscent of ferric iron stores in the brain. We report Aβ to be capable of accumulating iron(III) within amyloid aggregates, with this process resulting in Aβ-mediated reduction of iron(III) to a redox-active iron(II) phase. Additionally, we show that the presence of aluminium increases the reductive capacity of Aβ, enabling the redox cycling of the iron. These results demonstrate the ability of Aβ to accumulate iron, offering an explanation for previously observed local increases in iron concentration associated with AD lesions. Furthermore, the ability of iron to form redox-active iron phases from ferric precursors provides an origin both for the redox-active iron previously witnessed in AD tissue, and the increased levels of oxidative stress characteristic of AD. These interactions between Aβ and iron deliver valuable insights into the process of AD progression, which may ultimately provide targets for disease therapies.     

基于多感官交互的阿尔茨海默老人智能穿戴产品设计研究

目的 研究听觉、触觉与视觉多感官刺激因素介入阿尔茨海默病老人护理的反馈效果,借助智能软硬件技术增强其对音乐的感知,设计多感官交互的老人智能穿戴产品。方法 根据感知替换及通感原理,创建能够将音乐转化为振动及视觉信息的感官替代方法,并通过实验测试分别验证听–触觉和听–触–视觉两类多感官交互原型的可行性。结果 在融合听–触觉的基础上加入视觉设计,可以更好地激发老人的言语行为能力。在收集被试者使用反馈分析结论的基础上设计了一款指尖振动音乐可穿戴设备——指尖钢琴,通过提供以触觉、听觉、视觉融合的多感官体验来促进患者的主动行为。结论 多感官交互产品的设计对改善阿尔茨海默病患者的情绪和主动行为具有一定的效果,对老年患者身体健康和生活质量的提高具有积极意义。     

A validated predictive model of coronary fractional flow reserve

Myocardial fractional flow reserve (FFR), an important index of coronary stenosis, is measured by a pressure sensor guidewire. The determination of FFR, only based on the dimensions (lumen diameters and length) of stenosis and hyperaemic coronary flow with no other ad hoc parameters, is currently not possible. We propose an analytical model derived from conservation of energy, which considers various energy losses along the length of a stenosis, i.e. convective and diffusive energy losses as well as energy loss due to sudden constriction and expansion in lumen area. In vitro (constrictions were created in isolated arteries using symmetric and asymmetric tubes as well as an inflatable occluder cuff) and in vivo (constrictions were induced in coronary arteries of eight swine by an occluder cuff) experiments were used to validate the proposed analytical model. The proposed model agreed well with the experimental measurements. A least-squares fit showed a linear relation as (Δp or FFR)_experiment = a(Δp or FFR)_theory + b, where a and b were 1.08 and −1.15 mmHg (r² = 0.99) for in vitro Δp, 0.96 and 1.79 mmHg (r² = 0.75) for in vivo Δp, and 0.85 and 0.1 (r² = 0.7) for FFR. Flow pulsatility and stenosis shape (e.g. eccentricity, exit angle divergence, etc.) had a negligible effect on myocardial FFR, while the entrance effect in a coronary stenosis was found to contribute significantly to the pressure drop. We present a physics-based experimentally validated analytical model of coronary stenosis, which allows prediction of FFR based on stenosis dimensions and hyperaemic coronary flow with no empirical parameters.     

防治老年人阿尔茨海默症的益智关怀设计研

目的 结合对老年人阿尔茨海默症的调查研究、遵循适老设计原则,针对老年人防治该病设计一系列益智关怀产品。方法 通过调研法总结老年人生理、心理状态、致病因素以及生活习惯等,结合信息技术同时考虑易用性、安全性、趣味性等设计原则,对产品进行设计。结论 该设计从提供脑力锻炼方式、掌握阿尔茨海默症的前沿资讯、收集个人脑力健康数据几方面考虑,基于这几方面,该设计是一款带有训练游戏、实时资讯、脑力健康数据收集的智能APP,以及延伸出的适用于家里或社区活动中心的相关训练游戏实物产品。     

Crowdsourcing contest dilemma

Crowdsourcing offers unprecedented potential for solving tasks efficiently by tapping into the skills of large groups of people. A salient feature of crowdsourcing—its openness of entry—makes it vulnerable to malicious behaviour. Such behaviour took place in a number of recent popular crowdsourcing competitions. We provide game-theoretic analysis of a fundamental trade-off between the potential for increased productivity and the possibility of being set back by malicious behaviour. Our results show that in crowdsourcing competitions malicious behaviour is the norm, not the anomaly—a result contrary to the conventional wisdom in the area. Counterintuitively, making the attacks more costly does not deter them but leads to a less desirable outcome. These findings have cautionary implications for the design of crowdsourcing competitions.     

Evolution of the most common English words and phrases over the centuries

By determining the most common English words and phrases since the beginning of the sixteenth century, we obtain a unique large-scale view of the evolution of written text. We find that the most common words and phrases in any given year had a much shorter popularity lifespan in the sixteenth century than they had in the twentieth century. By measuring how their usage propagated across the years, we show that for the past two centuries, the process has been governed by linear preferential attachment. Along with the steady growth of the English lexicon, this provides an empirical explanation for the ubiquity of Zipf''s law in language statistics and confirms that writing, although undoubtedly an expression of art and skill, is not immune to the same influences of self-organization that are known to regulate processes as diverse as the making of new friends and World Wide Web growth.     

质量基准研究的最新进展

质量基准是迄今唯一保留人工制品的SI单位.近年来,计量学家通过国际合作,试图基于自然的不变性质、阿佛加德罗常数和普朗克常数的概念重新定义质量基准.     

基于KANO-AHP的阿尔兹海默症家庭服务系统设计研究

目的 在阿尔兹海默症患者家庭中,“陪伴”是最主要的日常行为,旨在探索KANO模型和AHP层次分析法在服务设计中的应用,以实现阿尔兹海默症家庭陪伴机器人及服务系统的创新设计。方法 综合分析智能陪伴产品及服务系统的研究现状,通过文献分析、焦点访谈、问卷调查等方法初步挖掘需求;运用KANO模型分析用户需求的特性;采用AHP层次分析法计算用户需求的权重值并进行重要性排序。基于这些分析,通过系统功能分析、界面设计及监护机器人设计,完成了阿尔兹海默症患者家庭服务系统的设计实践。结果 KANO模型识别出必要型、期望型、魅力型三类共10项需求指标。AHP法计算得出一级指标的权重优先级排序依次为心理关怀、健康管理、社交互动。进一步分析二级指标,发现用户对情绪管理、心理咨询、诊疗建议和解压活动的需求权重较高。结论 通过创新地将KANO-AHP结合的研究方法应用于阿尔兹海默症家庭服务系统的设计,提出了共情、实用、定制的设计原则。这些原则使产品和系统的设计更加科学合理,有助于提高用户满意度并为相关设计研究提供了新的方法与思路。