Commentary to the recently published review “Drug pipeline in neurodegeneration based on transgenic mice models of Alzheimer's disease” by Li,Evrahimi and Schluesener. Ageing Res. Rev. 2013 Jan;12(1):116–40

Li and colleagues summarized the most frequently used Alzheimer's disease (AD) mouse models available for drug testing and the mediating effects of the different compounds. With almost 300 cited publications, authors present the research community's effort of the last 10 years in finding a new drug for the treatment of AD.Some of the transgenic mouse lines mentioned by Li and colleagues are discussed only very briefly. Since we are convinced that a couple of these models indeed have a great value for AD research and the development of new AD drugs we will subsequently describe a few of them in more detail.A suitable mouse model of AD does not only have to mimic major hallmarks of AD that are modifiable by different test substances as mentioned by the authors; they also have to be translational to clinical trials in humans. For the following discussion, we will therefore also include information on clinical trials of drugs previously tested in the different transgenic mice.     

Current research status of blood biomarkers in Alzheimer’s disease: Diagnosis and prognosis

Alzheimer’s disease (AD), which mainly occurs in the elderly, is a neurodegenerative disease with a hidden onset, which leads to progressive cognitive and behavioral changes. The annually increasing prevalence rate and number of patients with AD exert great pressure on the society. No effective disease-modifying drug treatments are available; thus, there is no cure yet. The disease progression can only be delayed through early detection and drug assistance. Therefore, the importance of exploring associated biomarkers for the early diagnosis and prediction of the disease progress is highlighted. The National Institute on Aging— Alzheimer’s Association (NIA-AA) proposed A/T/N diagnostic criteria in 2018, including Aβ42, p-tau, t-tau in cerebrospinal fluid (CSF), and positron emission tomography (PET). However, the invasiveness of lumbar puncture for CSF assessment and non-popularity of PET have prompted researchers to look for minimally invasive, easy to collect, and cost-effective biomarkers. Therefore, studies have largely focused on some novel molecules in the peripheral blood. This is an emerging research field, facing many obstacles and challenges while achieving some promising results.     

基于MR图像纹理特征的阿尔茨海默病分类模型

目的基于MR图像,提取脑部海马区域纹理特征参数建立阿尔茨海默病(Alzheimer disease,AD)的早期分类预测模型。方法研究数据来源于美国国立老年研究所ADNI数据库,收集研究对象的磁共振(magnetic resonance,MR)脑图像,分别基于左、右和双侧海马图像,通过区域增长法和Contourlet变换提取纹理特征参数,结合研究对象的基本信息作为特征变量采用高斯过程分类方法建立AD患者和健康对照的诊断模型以及轻度认知障碍(mild cognitive impairment,MCI)患者转变为AD的预测模型,并评价模型的灵敏度、特异度以及ROC曲线下面积。结果研究共纳入420例研究对象。基于AD和健康对照两组构建的分类模型,双侧海马区的灵敏度、特异度以及ROC曲线下面积分别为92.7%、87.1%和0.922,均大于基于左侧或右侧海马区图像建立的模型。基于MCI数据建立的AD早期预测模型中,灵敏度最高为82.4%,ROC曲线下面积最高为0.836。结论基于脑部海马区的Contourlet纹理特征构建预测模型,可以识别AD早期的病变情况,这将有助于早期监测MCI进展为AD,为减缓和治疗AD发病提供依据。     

Corticosteroids, but not NSAIDs, are associated with less Alzheimer neuropathology

The objective of this study was to test the hypothesis that corticosteroid and nonsteroidal anti-inflammatory drug (NSAID) medications are associated with less global and regional Alzheimer's disease (AD) neuropathology. This postmortem study was based on 694 brains of subjects from the Mount Sinai School of Medicine Brain Bank who did not have neuropathologies other than neuritic plaques (NPs), neurofibrillary tangles (NFTs), or cerebrovascular disease. Densities of NPs and of NFTs were assessed in several neocortical regions and in the hippocampus, entorhinal cortex, and amygdala. Counts of NPs in several neocortical regions were also assessed. For each neuropathology measure, analyses of covariance controlling for age at death and sex compared subjects who received only corticosteroids (n = 54) or those who received only NSAIDs (n = 56) to the same comparison group, subjects who received neither (n = 576). Subjects receiving corticosteroids had significantly lower ratings and counts of NPs for all neuropathological measures, and NFTs overall and in the cerebral cortex and amygdala. In contrast, no measures were significant for subjects who received NSAIDs. Use of corticosteroids was associated with approximately 50% fewer NPs and NFTs in most brain regions examined, compared with nonmedicated subjects. In contrast, use of NSAIDs was not substantially associated with the reductions in hallmark lesions of AD. Because corticosteroids have anti-inflammatory as well as a myriad of other neurobiological effects, more direct studies in model systems could reveal novel therapeutic targets and mechanisms for AD lesion reduction.     

Automatic attentional shifts induced by a noradrenergic drug in Alzheimer's disease: evidence from evoked potentials.

Prior research showed that attentional deficits are observed in Alzheimer's disease (AD). These deficits can further impair other cognitive processes. The present experiment was designed to study the shifts in attention induced by a noradrenergic drug (S 12024-2) through their electrophysiological correlates in 12 outpatients with mild AD, using an auditory oddball paradigm. The P3a component, known to be related to automatic attentional processing, was increased by the drug, whereas no changes occurred either in PN or in P3b, which are considered to reflect conscious processing. These results point to an involvement of the noradrenergic system in the modulation of automatic attentional processing, and provide evidence for weakening of the orienting reflex in AD, due to a possible noradrenergic deficit in patients with mild AD.     

A comparative analysis of sensory visual evoked oscillations with visual cognitive event related oscillations in Alzheimer's disease

We compared visual evoked oscillatory responses of subjects with Alzheimer's disease (AD) (n = 22) to healthy elderly controls (n = 19) elicited by simple light stimuli. The visual evoked oscillatory responses in AD subjects without cholinergic treatment (n = 11) show significant differences (df = 2.38, F = 4.957, P = 0.012) from the controls and the AD subjects treated with a cholinesterase inhibitor (n = 11). Higher theta oscillatory responses in untreated AD subjects are seen on the electrode locations over bi-parietal and right occipital regions after simple light stimuli with less, if any, cognitive load. These changes were restricted to the theta frequency range only and are related to location, frequency bands and drug effects. In our previous work we observed that visual event related oscillations elicited after the visual stimuli with a higher cognitive load, i.e. an oddball target, display lower amplitudes: between controls and AD subjects in delta frequency band without a drug effect, over the left and mid-central region. These differences between the visual evoked oscillations and the visual event related oscillations imply that there are at least two different cognitive circuits that are activated upon visual stimuli in AD patients.     

DRD2/ANKK1 TaqIA and SLC6A3 VNTR polymorphisms in alcohol dependence: association and gene-gene interaction study in a population of Central Italy

Dopamine is a neurotransmitter whose functions are mediated by five receptors expressed in several organs and tissues. Dopaminergic system dysfunctions are involved in the etiology or treatment of several pathological conditions, including drug addiction. Alcohol dependence (AD) is a widespread psychiatric disorder, affecting 5.4% of the general population lifetime. Family and twins studies support the role of a genetic component in AD. Since dopamine neurotransmission has been shown to be involved in drug reward, related genes are plausible candidates for susceptibility to AD. Here, we evaluated both the DRD2/ANKK1 TaqIA (rs1800497) and SLC6A3 40 bp-VNTR SNP and gene-gene interaction analysis in AD patients from a population of Central Italy. The study design was a case-control. In total, 280 alcoholic subjects (213 men and 67 woman) and 280 age- and sex-matched control subjects were recruited for this study. Case subjects met the DSM-IV criteria for AD and they are free from any psychiatric co-morbidities. Controls were subjects who had non-alcohol problem either never drank; those who have smoked at least one pack of cigarettes per day for at least 1 year were excluded. Genotyping was performed by allele-specific PCR and RFLP-PCR. SLC6A3 40 bp 3'UTR-VNTR displays no association with AD. DRD2/ANKK1 TaqIA genotype distribution is significantly associated to AD (O.R.=1.551, p=0.023), with A1* allele displaying an O.R.=1.403 (p=0.029). Gene-gene interaction analysis using three-way contingency table analysis by a log-linear model yielded no significant result. Our study in a population of Central Italy extends and confirms previous results and, for the first time, tested the gene-gene interaction between SLC6A3 and DRD2 in AD.     

ADAS-Cog中文版区分轻、中度阿尔茨海默病的能力

目的：探讨阿尔茨海默病评定量表认知部分(ADAS-Cog)中文版区分轻、中度AD的能力。方法：199例轻度和106例中度AD患者为研究被试(符合NINCDS-ADRDA很可能AD诊断标准),对所有被试进行ADAS-Cog中文版测试。结果：中度AD患者ADAS-Cog总分及各条目评分明显高于轻度AD被试,GLM分析提示ADAS-Cog评分不受被试年龄与受教育程度的影响,ADAS-Cog能有效反映轻、中度AD患者不同的认知损害模式而不依赖于被试的学历。Logistic回归分析定向力和结构性练习条目评分及ADAS-Cog总分能有效区分轻、中度AD,敏感度为78％-82％,特异度为70％-73％。结论：ADAS-Cog中文版对轻、中度AD具有较好的区分能力,推荐将该量表用于评估药物对中国AD患者认知功能的疗效。     

Association between the interleukin-1alpha gene and Alzheimer's disease: a meta-analysis

Inflammatory processes are involved in the pathogenesis of Alzheimer's disease (AD). Several studies have addressed the effects of interleukin-1 (IL-1) genes polymorphisms on the risk of developing AD. The results are not in full agreement on whether these polymorphisms are associated with the disease. To clarify this issue, we performed a meta-analysis of all the association studies between IL-1 genes and AD. Due to the relatively small number of published articles, the meta-analysis was restricted to the association of the IL-1alpha -889 C/T gene polymorphism and AD. Under a random effects model, the risk for the disease was significantly higher in subjects with the T/T genotype in comparison with both C/T (OR: 1.51; 95% C.I.: 1.15-1.99) and C/C (OR: 1.49; 95% C.I.: 1.09-2.03) subjects. There was modest heterogeneity for these effect estimates. Analysis of subgroups showed a significant association in patients with early-onset AD but not in late-onset AD. Our data support a significant but modest association between the T/T genotype of the IL-1alpha gene and AD.     

No improvement after chronic ibuprofen treatment in the 5XFAD mouse model of Alzheimer's disease

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that has been reported to reduce the risk of developing Alzheimer's disease (AD). Its preventive effects in AD are likely pleiotropic as ibuprofen displays both anti-inflammatory activity by inhibition of cyclooxygenases and anti-amyloidogenic activity by modulation of γ-secretase. In order to study the anti-inflammatory properties of ibuprofen independent of its anti-amyloidogenic activity, we performed a long-term treatment study with ibuprofen in 5XFAD mice expressing a presenilin-1 mutation that renders this AD model resistant to γ-secretase modulation. As expected, ibuprofen treatment for 3 months resulted in a reduction of the inflammatory reaction in the 5XFAD mouse model. Importantly, an unchanged amyloid beta (Aβ) plaque load, an increase in soluble Aβ42 levels, and an aggravation of some behavioral parameters were noted, raising the question whether suppression of inflammation by nonsteroidal anti-inflammatory drug is beneficial in AD.     

Classification of diffusion tensor images for the early detection of Alzheimer's disease

Early detection of Alzheimer's disease (AD) is important since treatments are more efficacious when used at the beginning of the disease. Despite significant advances in diagnostic methods for AD, there is no single diagnostic method for AD with high accuracy. We developed a support vector machine (SVM) model that classifies mild cognitive impairment (MCI) and normal control subjects using probabilistic tractography and tract-based spatial statistics of diffusion tensor imaging (DTI) data. MCI is an intermediate state between normal aging and AD, so finding MCI is important for an early diagnosis of AD. The key features of DTI data we identified through extensive analysis include the fractional anisotropy (FA) values of selected voxels, their average FA value, and the volume of fiber pathways from a pre-defined seed region. In particular, the volume of the fiber pathways to thalamus is the most powerful single feature in classifying MCI and normal subjects regardless of the age of the subjects. The best performance achieved by the SVM model in a 10-fold cross validation and in independent testing was sensitivity of 100%, specificity of 100% and accuracy of 100%.     

Epigenome‐wide association studies in Alzheimer’s disease; achievements and challenges

Alzheimer’s disease (AD) represents a devastating progressive neurodegenerative disease with a complex pathophysiology, affecting millions of people worldwide. Recent epigenome‐wide association studies suggest a key role for epigenetic mechanisms in its development and course. Despite the fact that current evidence on the role of epigenetic dysregulation in aging and AD is convincing, the pioneering field of neuroepigenetics is still facing many challenges that need to be addressed to fundamentally increase our understanding about the underlying mechanisms of this neurodegenerative disorder. This perspective paper describes the current state of play for epigenetic research into AD and discusses how new methodological advances in the field of epigenetics and related data science disciplines could further spur the development of novel therapeutic agents and biomarker assays.     

Amyloid precursor proteins, neural differentiation of pluripotent stem cells and its relevance to Alzheimer's disease

Alzheimer's disease (AD) is a leading cause of age-related dementia that is characterized by an extensive loss of neurons and synaptic transmission. The pathological hallmarks of AD are neurofibrillary tangles and deposition of β-amyloid (Aβ) plaques. Previous research has investigated how Aβ fragments disrupt synaptic mechanisms in the vulnerable regions of the brain. There is a tremendous potential for stem cell technology to extend upon this research, not only in terms of developing therapeutic applications, but also in modeling AD. Indeed, the advent of induced pluripotent stem cell technology has opened up exciting new avenues for generating patient and disease-specific cell lines from somatic cells that may be used to model AD. Amyloid precursor protein (APP) is a key protein in neuronal development and this article reviews the role of APP in AD. Stem cell technology offers the opportunity to make use of APP in the directed differentiation of induced pluripotent stem cells into functional neurons, a process that may help generate a model of AD and thereby facilitate an understanding of the mechanisms underlying this disease.     

Biomarkers for major depression and its delineation from neurodegenerative disorders

Major depressive disorders (MDD) are among the most debilitating diseases worldwide and occur with a high prevalence in elderly individuals. Neurodegenerative diseases (in particular Alzheimer's disease, AD) do also show a strong age-dependent increase in incidence and prevalence among the elderly population. A high number of geriatric patients with MDD show cognitive deficits and a very high proportion of AD patients present co-morbid MDD, which poses difficult diagnostic and prognostic questions. Especially in prodromal and in very early stages of AD, it is almost impossible to differentiate between pure MDD and MDD with underlying AD.Here, we give a comprehensive review of the literature on the current state of candidate biomarkers for MDD (“positive MDD markers”) and briefly refer to established and validated diagnostic AD biomarkers in order to rule out underlying AD pathophysiology in elderly MDD subjects with cognitive impairments (“negative MDD biomarkers”). In summary, to date there is no evidence for positive diagnostic MDD biomarkers and the only way to delineate MDD from AD is to use “negative MDD” biomarkers.Because of this highly unsatisfactory current state of MDD biomarker research, we propose a research strategy targeting to detect and validate positive MDD biomarkers, which is based on a complex (genetic, molecular and neurophysiological) biological model that incorporates current state of the art knowledge on the pathobiology of MDD. This model delineates common pathways and the intersection between AD and MDD. Applying these concepts to MDD gives hope that positive MDD biomarkers can be successfully identified in the near future.     

Biomarkers for major depression and its delineation from neurodegenerative disorders

Major depressive disorders (MDD) are among the most debilitating diseases worldwide and occur with a high prevalence in elderly individuals. Neurodegenerative diseases (in particular Alzheimer's disease, AD) do also show a strong age-dependent increase in incidence and prevalence among the elderly population. A high number of geriatric patients with MDD show cognitive deficits and a very high proportion of AD patients present co-morbid MDD, which poses difficult diagnostic and prognostic questions. Especially in prodromal and in very early stages of AD, it is almost impossible to differentiate between pure MDD and MDD with underlying AD. Here, we give a comprehensive review of the literature on the current state of candidate biomarkers for MDD ("positive MDD markers") and briefly refer to established and validated diagnostic AD biomarkers in order to rule out underlying AD pathophysiology in elderly MDD subjects with cognitive impairments ("negative MDD biomarkers"). In summary, to date there is no evidence for positive diagnostic MDD biomarkers and the only way to delineate MDD from AD is to use "negative MDD" biomarkers. Because of this highly unsatisfactory current state of MDD biomarker research, we propose a research strategy targeting to detect and validate positive MDD biomarkers, which is based on a complex (genetic, molecular and neurophysiological) biological model that incorporates current state of the art knowledge on the pathobiology of MDD. This model delineates common pathways and the intersection between AD and MDD. Applying these concepts to MDD gives hope that positive MDD biomarkers can be successfully identified in the near future.     

Apolipoprotein E, cholesterol transport and synthesis in sporadic Alzheimer's disease

The discovery that the apolipoprotein E4 (apoE4) allele is genetically linked to both sporadic and familial late onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system could seriously affect lipid homeostasis in the brain of AD subjects. The presence of the E4 allele has been associated with lower levels of apoE in both serum and brain tissues of normal and AD subjects. In an attempt to reverse the apoE deficit in AD, we identified and characterized several apoE inducer agents using a low throughput-screening assay. The most promising of these compounds is called probucol. Administration of probucol, an old cholesterol lowering drug, in mild to moderate sporadic AD led to significant increases in CSF apoE levels and a decrease of CSF beta amyloid 1-42 without significant modifications of CSF tau concentration or CSF lipid peroxides levels. These results are consistent with recent reports suggesting that the long term use of cholesterol lowering drugs that block 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity in the fourth and fifth decade of life may help reduce the risk of developing AD at later age. These results indicate that, in addition to lipid transport mediated by apoE, cholesterol homeostasis in the brain is markedly altered in response to changes in the HMGR pathway; suggesting a possible explanation for the potentially beneficial effect of statins in common AD.     

阿尔茨海默病新药的临床实验研究

痴呆是一种以认知功能缺损为核心症状的获得性智能损害综合症,属于慢性进展性疾病,严重影响患者的生活质量。导致痴呆的疾病中阿尔茨海默病（AD）占3/4,其余还包括血管性痴呆（VaD）、混合型痴呆、路易体痴呆、额颞叶痴呆等。AD已成为影响我国经济社会发展的重大公共卫生健康问题和社会问题,但目前为止,获得批准治疗AD的药物只有胆碱酯酶抑制剂和NMDA受体拮抗剂两类,这些药物只能控制症状,而无法达到疾病修饰治疗（DMT）的效果。此外,国外最近十年被批准进行的AD临床实验较少,且失败率较高,目前尚未开发出具有DMT效果的AD治疗药物。本文从AD相关的神经退行性病理变化、AD相关临床实验研究作一综述,为开发新的AD治疗靶点提供参考依据。     

Whole brain atrophy rate predicts progression from MCI to Alzheimer's disease

For both clinical and research reasons, it is essential to identify which mild cognitive impairment (MCI) subjects subsequently progress to Alzheimer's disease (AD). The prediction may be facilitated by accelerated whole brain atrophy exhibited by AD subjects. Iterative principal component analysis (IPCA) was used to characterize whole brain atrophy rates using sequential MRI scans for 102 MCI subjects from the Kuopio University Hospital. We modelled the likelihood of progression to probable AD, and found that each additional percent of annualized whole brain atrophy rate was associated with a higher odds ratio (OR) of progression (OR=1.30, p=0.01, 95% CI=1.05-1.60). Our study demonstrates an association between whole brain atrophy rate and subsequent rate of clinical progression from MCI to AD. These findings suggest that IPCA could be an effective brain-imaging marker of progression to AD and useful tool for the evaluation of disease-modifying treatments.     

The capillary dysfunction hypothesis of Alzheimer's disease

It is widely accepted that hypoperfusion and changes in capillary morphology are involved in the etiopathogenesis of Alzheimer's disease (AD). This is difficult to reconcile with the hyperperfusion observed in young high-risk subjects. Differences in the way cerebral blood flow (CBF) is coupled with the local metabolic needs during different phases of the disease can explain this apparent paradox. This review describes this coupling in terms of a model of cerebral oxygen availability that takes into consideration the heterogeneity of capillary blood flow patterns. The model predicts that moderate increases in heterogeneity requires elevated CBF in order to maintain adequate oxygenation. However, with progressive increases in heterogeneity, the resulting low tissue oxygen tension will require a suppression of CBF in order to maintain tissue metabolism. The observed biphasic nature of CBF responses in preclinical AD and AD is therefore consistent with progressive disturbances of capillary flow patterns. Salient features of the model are discussed in the context of AD pathology along with potential sources of increased capillary flow heterogeneity.     

Diagnosis and biomarkers of predementia in Alzheimer's disease

In view of the growing prevalence of Alzheimer's disease (AD) worldwide, there is an urgent need for the development of better diagnostic tools and more effective therapeutic interventions. At the earliest stages of AD, no significant cognitive or functional impairment is detected by conventional clinical methods. However, new technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid (CSF) may reveal correlates of intracerebral pathology in individuals with mild, predementia symptoms. These putative correlates are commonly referred to as AD-related biomarkers. The relevance of the early diagnosis of AD relies on the hypothesis that pharmacological interventions with disease-modifying compounds are likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. Here we review the clinical characteristics of the prodromal and transitional states from normal cognitive ageing to dementia in AD. We further address recent developments in biomarker research to support the early diagnosis and prediction of dementia, and point out the challenges and perspectives for the translation of research data into clinical practice.