Mild cognitive impairment and preclinical Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by a gradual decline of numerous cognitive processes, culminating in dementia. Mild cognitive impairment (MCI) is a relatively broad clinical condition involving a slight memory deficit, which in many cases represents a transitional state between normal cognition and AD. Much research is currently being conducted on MCI, since any therapy that is effective at treating this early manifestation of dementia may provide an opportunity for managing the disease while patient function is relatively preserved. Current research seeks to develop disease-modifying treatments that intervene in the pathobiologic processes involved in MCI and AD. Another goal of current research is to develop antecedent biomarkers that can be used to detect AD prior to the appearance of symptoms and before substantial and irreversible brain damage occurs.     

Near a biological diagnosis of Alzheimer's disease and related disorders

PURPOSE: To review the current concepts in the biological diagnosis of Alzheimer's disease (AD) and related disorders. CURRENT KNOWLEDGE AND KEY POINTS: As new therapeutics specific of AD may be available soon, early diagnosis of AD in the context of mild cognitive impairment (MCI) or dementia appears to be challenging. The high amount of atypical clinical forms of AD leads to develop new tools allowing in vivo diagnosis. New CerebroSpinal Fluid (CSF) biomarkers seem to reflect specific aspects of deep neuropathological changes observed in AD, i.e. amyloid deposits and neurofibrillary tangles. Amyloid beta-peptide 1-42 (Abeta(1-42)) and hyperphosphorylated tubulin associated unit (tau) isoforms appear to be the most sensitive and specific CSF biomarkers, the combination of these biomarkers depicting the best diagnosis value for AD. These molecules are also efficient in the prediction of the conversion from the MCI state to the dementia state of AD. Combined to clinical and neuro-imaging information, CSF biomarkers appear thus to be highly relevant in improving the early etiological diagnosis of dementia. FUTURE PROSPECTS AND PROJECTS: The current research focalises on the development of new molecules coming from Abeta and tau protein families, in the CSF and in the serum, as well as molecules reflecting other pathological metabolism changes, as alpha-synuclein in Lewy Body Disease. The diagnosis value of CSF biological markers is so promising that they have been recently included in the research diagnosis criteria of AD.     

从阿尔茨海默病新诊断指南看轻度认知功能损害概念的变化

阿尔茨海默病（AD）是以认知功能损害为突出表现的神经系统退变性疾病。轻度认知功能障碍（MCI）是认知功能低于同龄及文化背景的正常人但未达到痴呆程度的认知功能损害状态,被认为是痴呆、特别是AD的危险因素。临床及流行病学的研究表明MCI存在着异质性,有关MCI的概念及转归一直存在争论。随着对AD痴呆前阶段的关注,有必要了解MCI的含义及其变化。本文复习了MCI概念的提出、定义及其内容上发生的变化,并介绍了新的NIA—AD工作组AD诊断指南。     

Early identification of cognitive deficits: preclinical Alzheimer's disease and mild cognitive impairment

With the projected dramatic increase in the number of people who will be diagnosed with Alzheimer's disease (AD) in the coming years, interest is growing in identifying and treating adults at high risk for developing the disorder. Recent research suggests that individuals who will go on to receive a diagnosis of AD exhibit deficits in cognitive performance years beforehand. Those with mild cognitive impairment (MCI), for example, have characteristic cognitive deficits, such as memory loss, and convert to a diagnosis of AD at a faster rate than cognitively healthy controls. MCI has thus become a focus of research because it may help identify high-risk individuals for whom prophylactic treatments designed to slow the progress toward AD can be prescribed. After describing the diagnostic criteria and dementia outcomes associated with MCI, this article discusses several challenges to the study of cognitive impairment before the diagnosis of AD.     

轻度认知障碍

1引言1．1背景轻度认知障碍,尤其是在患者自己报告时,向临床医生提出了实质性的挑战。医生们可能在处理某一轻度或短暂性疾病、某种药物引起的不良反应或某种抑郁症的患者时,该患者可能处于最终将导致     

Mild cognitive impairment as a diagnostic entity

The concept of cognitive impairment intervening between normal ageing and very early dementia has been in the literature for many years. Recently, the construct of mild cognitive impairment (MCI) has been proposed to designate an early, but abnormal, state of cognitive impairment. MCI has generated a great deal of research from both clinical and research perspectives. Numerous epidemiological studies have documented the accelerated rate of progression to dementia and Alzheimer's disease (AD) in MCI subjects and certain predictor variables appear valid. However, there has been controversy regarding the precise definition of the concept and its implementation in various clinical settings. Clinical subtypes of MCI have been proposed to broaden the concept and include prodromal forms of a variety of dementias. It is suggested that the diagnosis of MCI can be made in a fashion similar to the clinical diagnoses of dementia and AD. An algorithm is presented to assist the clinician in identifying subjects and subclassifying them into the various types of MCI. By refining the criteria for MCI, clinical trials can be designed with appropriate inclusion and exclusion restrictions to allow for the investigation of therapeutics tailored for specific targets and populations.     

简易认知量表和8条目痴呆筛查问卷在高龄老年人群早期认知功能下降筛查中的应用

目的探讨简易认知量表（Mini-Cog）和8条目痴呆筛查问卷（8-item ascertain dementia, AD8）对80岁以上老年人群早期轻度认知功能障碍（mild cognitive impairment, MCI）的筛查价值。 方法选取杭州市某福利中心的2014年10月前已入住的908名高龄老年人进行Mini-Cog和AD8筛查,随访5年后对仍然健在且能配合完成检查者进行二次认知功能评估。计算Mini-Cog和AD8初筛的敏感度和特异度,并分析随访5年后AD8的ROC曲线结果以及两种量表的一致性检验结果。 结果908例高龄老年人中523例确诊为痴呆（不计入后续筛查及随访调查）,余385例筛查结果显示：Mini-Cog、AD8诊断MCI的敏感度分别为54.88%、57.32%,特异度分别为85.52%、86.43%。随访5年后仍健在且接受二次评估的老年人共167名,其中认知功能正常106例（54例出现认知功能下降）,MCI 61例（36例出现认知功能进一步下降）。对于随访5年的认知功能正常者及MCI者,AD8诊断的AUC分别为0.572（95%CI=0.486-0.658）、0.723（95%CI=0.611-0.835）,Mini-Cog和AD8（以得分>3为分界线）诊断的一致性Kappa值分别为0.105、0.018和0.225、0.524。 结论AD8和Mini-Cog均具有一定的MCI评估效能,尤其适用于养老机构及社区高龄老年群体的认知功能筛查。     

Growth factors and cytokines/chemokines as surrogate biomarkers in cerebrospinal fluid and blood for diagnosing Alzheimer’s disease and mild cognitive impairment

Alzheimer’s disease (AD) is a severe chronic neurodegenerative disorder of the brain. A probable diagnosis of AD can be obtained by cerebrospinal fluid levels of 3 biomarkers: beta-amyloid (1–42), total tau and phospho-tau181. Researchers are interested in finding additional biomarkers in CSF to improve the specificity and sensitivity of diagnosis, including also other forms of dementia, such as mild cognitive impairment (MCI). In addition, less invasive diagnostic methods using blood or blood-derived cells are being investigated. This mini-review (in concert with the other reviews of this special issue) summarizes the usefulness of growth factors and cytokines/chemokines as putative surrogate biomarkers for diagnosing AD and MCI in CSF and blood. Briefly, the expression levels of growth factors and cytokines/chemokines are very heterogenous, indicating the pathological diversity of these diseases. At present, no single growth factor or cytokine alone stands out as a useful biomarker for diagnosing AD or MCI. However, the combined “patients profile signature” of several selected growth factors and/or cytokines/chemokines may allow to diagnose AD and MCI with higher selectively and specificity.     

Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies

This study examined the association of diabetes with the onset of dementia (including Alzheimer's disease (AD), vascular dementia (VD) and any dementia) and mild cognitive impairment (MCI) by using a quantitative meta-analysis of longitudinal studies. EMBASE and MEDLINE were searched for articles published up to December 2010. All studies that examined the relationship between diabetes and the onset of dementia or MCI were included. Pooled relative risks were calculated using fixed and random effects models. Nineteen studies met our inclusion criteria for this meta-analysis, and 6184 subjects with diabetes and 38 530 subjects without diabetes were included respectively. All subjects were without dementia or MCI at baseline. The quantitative meta-analysis showed that subjects with diabetes had higher risk for AD (relative risk (RR):1.46, 95% confidence interval (CI): 1.20-1.77), VD (RR: 2.48, 95% CI: 2.08-2.96), any dementia (RR: 1.51, 95% CI: 1.31-1.74) and MCI (RR: 1.21, 95% CI: 1.02-1.45) than those without. The quantitative meta-analysis showed that diabetes was a risk factor for incident dementia (including AD, VD and any dementia) and MCI.     

轻度认知损害患者的静息态功能磁共振成像

识别轻度认知损害(mild cognitive impairment,MCI)的意义在于能尽早进行干预并推迟甚至阻止其进展为痴呆.不过,由于受到诊断方法和标准的限制,MCI患者的诊断较为困难.近年来,静息态功能磁共振成像(resting-state functional magnetic resonance imaging,rs-fMRI)作为一种新兴的功能影像学技术得到迅速发展,被广泛应用于MCI的研究,有可能为MCI的诊断提供客观的生物学标记物.文章就rs-fMRI在MCI中的研究进展进行了综述.     

CSF biomarkers for mild cognitive impairment

A correct clinical diagnosis of Alzheimer's disease (AD) early in the course of the disease is of importance to initiate symptomatic treatment with acetylcholine esterase inhibitors, and will be even more important when disease-arresting drugs, such as beta-sheet breakers or gamma-secretase inhibitors, will reach the clinic. However, there is no clinical method to determine if a patient with mild cognitive impairment (MCI) has incipient AD, i.e. will progress to AD with dementia, or have a benign form of MCI without progression. Thus, there is a great clinical need for diagnostic biomarkers to identify incipient AD in MCI cases. Three cerebrospinal fluid (CSF) biomarkers; total-tau (T-tau), phospho-tau (P-tau) and the 42 amino acid form of beta-amyloid (Abeta42) have been evaluated in numerous scientific papers. These CSF markers have high sensitivity to differentiate early and incipient AD from normal ageing, depression, alcohol dementia and Parkinson's disease, but lower specificity against other dementias, such as frontotemporal and Lewy body dementia. However, if the CSF biomarkers are used in the right clinical context, i.e. together with the cumulative information from the clinical examination, standard laboratory tests and brain-imaging techniques [single photon emission tomography (SPECT) and magnetic resonance tomography (MRT) scans], they may have a role in the clinical evaluation of MCI cases.     

Role of cardiovascular risk factors (CRF) in the patients with mild cognitive impairment (MCI)

Few therapeutic options are available nowadays to improve the prognosis of patients with Alzheimer's disease (AD). There are rather several evidences in literature that controlling vascular risk factors may be an effective intervention for modifying the course of this disease. The aim of our study was to investigate the role of CRF in 50 patients with MCI according to Petersens's criteria, and to evaluate their influence on cognitive and behavioral features of the disease and on the development of dementia. Statistical analysis of the data showed that the 60% of the patients with MCI and CRF developed dementia, while 40% maintained the same cognitive conditions at the end of the study. Only 32% of the subjects without cardiovascular comorbidities developed dementia. The results of the study suggest that CRF play a key role in cognitive decline of patients with MCI. Patients with MCI and CRF showed not only worse cognitive performances, but also behavioral disorders, depression and functional disability. Patients with CRF had higher conversion rate to AD than the other group, with a mean disease-free period 3 months shorter than the control group.     

轻度认知功能障碍向阿尔茨海默病转化的预测研究进展

轻度认知功能障碍（MCI）是介于正常衰老与痴呆之间的认知功能缺损状态,MCI进展为阿尔茨海默病（AD）的危险性较高,故MCI阶段可能是进行AD预防性治疗的最合适阶段,因而成为研究的焦点。本文就近年来MCI向AD的转化预测研究做一综述,主要包括五个方面：神经心理学测试、生物标志物检查、神经影像学检查、脑电生理学检查及其治疗进展。     

Early detection of Alzheimer's disease using neuroimaging

Neuroimaging is being increasingly used to complement clinical assessments in the early detection of Alzheimer's disease (AD). Structural magnetic resonance imaging (MRI) and metabolic positron emission tomography (FDG-PET) are the most clinically used and promising modalities to detect brain abnormalities in individuals who might be at risk for AD but who have not yet developed symptoms. The knowledge of established risk factors for AD enabled investigators to develop enrichment strategies for longitudinal imaging studies to reduce the sample sizes and study duration. The present review focuses on the results obtained by MRI and FDG-PET studies that examined the preclinical AD stages in several at risk populations: (1) individuals from families with autosomal dominant early-onset AD (FAD), (2) patients with mild cognitive impairment (MCI), particularly in memory, who are at very high risk for declining to AD with an estimated decline rate of 10-30% per year, (3) normal young and middle-age subjects carriers of known susceptibility genes for late-onset AD such as the Apolipoprotein E (ApoE) E4 allele, and (4) as age is the main risk factor for AD, normal elderly individuals followed to the onset of MCI and AD. Overall, these studies show that the use of imaging for the early detection of AD is successful even in the earlier stages of disease when clinical symptoms are not fully expressed and the regional brain damage may be limited.     

Assessing adipokines as potential biomarkers of dementia,Alzheimer's disease,and mild cognitive impairment: A systematic review and meta-analysis

Midlife obesity and late-life weight loss confer a greater risk for developing dementia and Alzheimer's disease (AD), but the exact mechanisms behind this phenomenon are currently unknown. The answer could lie on the involvement of gastrointestinal factors, such as adipokines (e.g., leptin, adiponectin, and resistin) and ghrelin. In this context, we conducted a pre-registered systematic review and meta-analysis of 42 cross-sectional and 13 longitudinal studies targeting the associations between leptin, adiponectin, resistin, and ghrelin and the prevalence of general dementia, AD, and mild cognitive impairment (MCI). We also examined the relationship between the four gastrointestinal factors and neurocognitive outcomes and AD-related cerebrospinal fluid biomarkers. Patients with AD had lower blood leptin and higher resistin levels than cognitively normal participants. Lower leptin and higher resistin were associated with higher degree of cognitive impairment. Additionally, lower late-life leptin levels might be associated with higher prospective risk of dementia and AD, although more studies are needed to corroborate this. Results in ghrelin and adiponectin were not conclusive, with age, sex distribution, obesity, and severity of dementia seemingly acting as moderators across several analyses. Our work might contribute to the identification of new preclinical blood markers of MCI and AD.     

From mild cognitive impairment to prodromal Alzheimer disease: A nosological evolution

Despite of the positive medical and scientific advances generated through the mild cognitive impairment (MCI) diagnosis, as we will see along this paper, the concept of MCI presents several major limitations. MCI defines a syndrome and therefore it may be the consequence of different diseases with distinct aetiologies. Furthermore, the philosophy behind the MCI scenario has been to detect a group of symptoms that eventually will evolve into a distinct disease. In contrast, our nowadays aim is to detect a disease in its earlier stages that eventually will evolve from one clinical syndrome to another. As an example, our aim now is to detect early AD that initially will manifest as a memory syndrome and eventually will evolve into a dementia syndrome. Consequently, in order to overcome the syndromical diagnosis behind MCI, the concept of prodromal AD (Prd-AD) has recently emerged. Prd-AD is defined as the symptomatic predementia phase of AD, generally included in the MCI category; this stage is characterised by symptoms not severe enough to meet currently accepted diagnostic criteria for AD. Being a nosological concept, it has several potential advantages related with early diagnosis and treatment, together with the possibility to contribute to the development of disease modifying drugs.     

Gene expression analysis of cardiovascular diseases: novel insights into biology and clinical applications

Although the contribution of genetics to complex cardiovascular diseases such as atherosclerosis has been accepted for quite some time, full and detailed knowledge of the individual causative genes has been elusive. With the advent of genomic technologies and methods, the necessary tools are now available to begin pinpointing the genes that contribute to disease susceptibility and progression. One approach being applied extensively in candidate gene discovery is gene expression analysis of human and animal tissues using microarrays. The genes identified by these genomic studies provide valuable insight into disease biology and represent the initial steps toward the development of diagnostic tests and therapeutic strategies that will substantially improve human health. This paper highlights the progress that has been made in using gene expression analysis cardiovascular genomic research and the potential for applying these findings in clinical medicine.     

Gene expression analysis of cardiovascular diseases: novel insights into biology and clinical applications.

Although the contribution of genetics to complex cardiovascular diseases such as atherosclerosis has been accepted for quite some time, full and detailed knowledge of the individual causative genes has been elusive. With the advent of genomic technologies and methods, the necessary tools are now available to begin pinpointing the genes that contribute to disease susceptibility and progression. One approach being applied extensively in candidate gene discovery is gene expression analysis of human and animal tissues using microarrays. The genes identified by these genomic studies provide valuable insight into disease biology and represent the initial steps toward the development of diagnostic tests and therapeutic strategies that will substantially improve human health. This paper highlights the progress that has been made in using gene expression analysis cardiovascular genomic research and the potential for applying these findings in clinical medicine.     

Atrial fibrillation and risk of dementia in non-demented elderly subjects with and without mild cognitive impairment (MCI)

MCI is regarded as a precursor of dementia, but not all patients with MCI actually develop dementia. As Alzheimer and vascular dementia (AD and VD, respectively) are thought to share many common etiopathogenetic mechanisms, we investigated whether the vascular risk factor atrial fibrillation affect the risk of conversion to dementia for different MCI subtypes diagnosed according to international criteria. One-hundred-eighty elderly outpatients with MCI and 431 elderly outpatients with a normal cognition were followed-up for a mean of 3 and 4 years, respectively. The risk of conversion to dementia associated with atrial fibrillation was studied in both samples using a Cox proportional-hazards model adjusted for sociodemographic and medical variables. Overall conversion rate to dementia was 10.5 (8.0-13.8) per 100 person-years in the MCI group and 2.2 (1.5-3.1) per 100 person-years in the normal cognition group. Atrial fibrillation was significantly associated with conversion to dementia (hazard ratio=HR=4.63, 95% confidence interval=Cl=1.72-12.46) in the MCI group, but not in the cognitively normal group (HR=1.10, 95% Cl=0.40-3.03). Current diagnostic criteria for MCI subtypes define heterogeneous populations, but atrial fibrillation can be useful in identifying people with increased risk of conversion to dementia.