CSF tau and β-amyloid as biomarkers for mild cognitive impairment

Early diagnosis of Alzheimer s disease (AD) is relevant in order to initiate symptomatic treatment with antidementia drugs. This will be of greater significance if the drugs aimed at slowing down the degenerative process (secondary prevention) prove to affect AD pathology and are clinically effective, such as γ-secretase inhibitors. However, there is currently no clinical assessment to differentiate the patients with mild cognitive impairment (MCI) who will progress to AD from those with a benign form of memory impairment that is part of the normal aging process. Thus, there is great clinical need for diagnostic and predictive biomarkers, as well as biomarkers for classification purposes, to identify incipient AD in MCI subjects. The most promising cerebrospinal fluid (CSF) biomarker candidates are total tau protein (T-tau), phosphorylated tau protein (P-tau), and the 42-andno acid form offi-amyloid (Aβ42), which may, if used in the right clinical context, prove to have sufficient diagnostic accuracy and predictive power to resolve this diagnostic challenge.     

Structural neuroimaging in Alzheimer's disease: do white matter hyperintensities matter?

The targeted brain dysfunction that accompanies aging can have a devastating effect on cognitive and intellectual abilities. A significant proportion of older adults experience precipitous cognitive decline that negatively impacts functional activities. Such individuals meet clinical diagnostic criteria for dementia, which is commonly attributed to Alzheimer''s disease (AD). Structural neuroimaging, including magnetic resonance imaging (MRI), has contributed significantly to our understanding of the morphological and pathology-related changes that may underlie normal and disease-associated cognitive change in aging. White matter hyperintensities (WMH), which are distributed patches of increased hyperintense signal on T2-weighted MRI, are among the most common structural neuroimaging findings in older adults. In recent years, WMH have emerged as robust radiological correlates of cognitive decline. Studies suggest that WMH distributed in anterior brain regions are related to decline in executive abilities that is typical of normal aging, whereas WMH distributed in more posterior brain regions are common in AD. Although epidemiological, observational, and pathological studies suggest that WMH may be ischemic in origin and caused by consistent or variable hypoperfusion, there is emerging evidence that they may also reflect vascular deposition of (β-amyloid, particularly when they are distributed in posterior areas and are present in patients with AD. Findings from the literature highlight the potential contribution of small-vessel cerebrovascular disease to the pathogenesis of AD, and suggest a mechanistic interaction, but future longitudinal studies using multiple imaging modalities are required to fully understand the complex role of WMH in AD.     

Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer's disease

Alzheimer''s disease (AD) is the most common form of age-related dementias. In addition to genetics, environment, and lifestyle, growing evidence supports vascular contributions to dementias including dementia because of AD. Alzheimer''s disease affects multiple cell types within the neurovascular unit (NVU), including brain vascular cells (endothelial cells, pericytes, and vascular smooth muscle cells), glial cells (astrocytes and microglia), and neurons. Thus, identifying and integrating biomarkers of the NVU cell-specific responses and injury with established AD biomarkers, amyloid-β (Aβ) and tau, has a potential to contribute to better understanding of the disease process in dementias including AD. Here, we discuss the existing literature on cerebrospinal fluid biomarkers of the NVU cell-specific responses during early stages of dementia and AD. We suggest that the clinical usefulness of established AD biomarkers, Aβ and tau, could be further improved by developing an algorithm that will incorporate biomarkers of the NVU cell-specific responses and injury. Such biomarker algorithm could aid in early detection and intervention as well as identify novel treatment targets to delay disease onset, slow progression, and/or prevent AD.     

Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges

No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer''s disease (AD) and Parkinson''s disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.     

Imaging in Alzheimer's disease

Neuroimaging in the early differential diagnosis of dementia has gained considerable interest over the last decade. From being used for exclusive purposes only, neuroimaging is now in the forefront of aiding in the diagnosis of Alzheimer''s disease (AD), frontotemporal dementia, vascular dementia, and and dementia with Lewy bodies (DLB). With the exception of dopamine transporter single photon-emission computed tomography imaging in DLB, imaging has not yet been incorporated into the diagnostic criteria for the various dementia syndromes, but that will soon change. The recently formulated research criteria for early AD recently formulated by Dubois et al explicitly mention magnetic resonance imaging and positron emission tomography for AD, and are an example of a new diagnostic process developing. In this review, the various imaging techniques will be highlighted, with an emphasis on their ability to diagnose Alzheimer''s disease and separate it from other entities.     

Novel strategies for the prevention of dementia from Alzheimer's disease

As the world''s population continues to age, Alzheimer''s disease presents a homing public health crisis that left unchecked, threatens to overwhelm health care systems throughout the developed world, in order to significantly tackle the most catastrophic and devastating symptom of Alzheimer''s disease (AD)-dementia-we must be able to detect the disease prior to the onset of clinical symptoms, and be able to offer patients preventative treatments that block or significantly slow disease progression. This review summarizes a variety of the most promising early detection methods for Alzheimer''s disease (AD) and mild cognitive impairment (MCI) that could be used to identify those at high risk of developing the disease and used for monitoring disease progression and response to investigational treatments, in addition, treatment research programs that could be developed into disease-modifying treatments that significantly delay the development of dementia are highlighted. These potential treatments target many different pathways, and may one day be dosed in combination to increase efficacy and prevent cognitive deterioration in patients with AD. While we still face numerous challenges, AD researchers have made great progress in understanding disease mechanisms. As we have seen in the treatment of heart disease, even modest preventative treatments can have hugely significant clinical outcomes and drastically reduce disease prevalence on a population scale. Therefore, there is hope that the development of prophylactic treatments, combined with improved early detection methods, will provide dramatic relief for millions of aging individuals threatened by the specter of Alzheimer''s disease.     

Biomarkers Predicting Alzheimer's Disease in Cognitively Normal Aging

The pathophysiologic process of Alzheimer''s disease (AD) begins years before the diagnosis of clinical dementia. This concept of preclinical AD has arisen from the observation of AD pathologic findings such as senile plaques and neurofibrillary tangles in the brains of people who at the time of death had normal cognitive function. Recent advances in biomarker studies now provide the ability to detect the pathologic changes of AD, which are antecedent to symptoms of the illness, in cognitively normal individuals. Functional and structural brain alterations that begin with amyloid-β accumulation already show the patterns of abnormality seen in individuals with dementia due to AD. The presence of preclinical AD provides a critical opportunity for potential interventions with disease-modifying therapy. This review focuses on the studies of antecedent biomarkers for preclinical AD.     

Inflammation and the pathophysiology of Alzheimer's disease

There is increasing evidence that a chronic inflammatory response in the brain in Alzheimer's disease (AD) ultimately leads to neuronal injury and cognitive decline. Microglia, the primary immune effector cells of the brain, are thought to be key to this process. This paper discusses the evidence for inflammation in AD, and describes the mechanism whereby microglia generate neurotoxic cytokines, reactive oxygen species, and nitric oxide. Evidence that the cytokine macrophage colony-stimulating factor (M-CSF) is an important cofactor in microglial activation in AD is presented. Ongoing work using organotypic hippocampal expiant cultures to model the inflammatory process in the AD brain is also discussed. Potential avenues for therapeutic intervention are outlined.     

Early diagnosis of Alzheimer's disease: update on combining genetic and brain-imaging measures

Diagnosis of Alzheimer's disease is often missed or delayed in clinical practice; thus, methods to improve early detection would provide opportunities for early intervention, symptomatic treatment, and improved patient function. Emerging data suggest that the disease process begins years before clinical diagnostic confirmation. This paper reviews current research focusing on methods for more specific and sensitive early detection using measures of genetic risk for Alzheimer's disease and functional brain imaging. This approach aims to identify patients in a presymptomatic stage for early treatment to delay progressive cognitive decline and disease onset.     

Predictive value of platelet activation for the rate of cognitive decline in Alzheimer's disease patients

Vascular risk factors contribute to the progression of dementia in Alzheimer''s disease (AD) and influence platelet activation. However, the degree of platelet activation as a possible underlying mechanism of this progression has not been studied till now. Significantly higher baseline expression of both platelet activation biomarkers, activated glycoprotein IIb–IIIa complex and P-selectin, was observed in patients with AD with fast cognitive decline compared with AD patients with slow cognitive decline during a 1-year follow-up period. These results suggest that platelet activation could be a putative prognostic biomarker for the rate of cognitive decline and a potential new treatment target in AD patients.     

A Consensus in Korea Regarding a Protocol to Reduce Preanalytical Sources of Variability in the Measurement of the Cerebrospinal Fluid Biomarkers of Alzheimer's Disease

Cerebrospinal fluid (CSF) can provide vital informative about pathological processes occurring in the brain. In particular, the CSF concentrations of Aβ42, tTau, and pTau181 are useful for the early diagnosis of Alzheimer''s disease (AD). However, many studies have demonstrated that confounding factors related to the preanalytical processing of CSF can seriously influence measurements of these AD biomarkers. It is therefore important to develop a standardized protocol for the acquisition and handling of CSF, particularly with regard to the types of tube used for collection and storage, the proper aliquot volume, blood contamination, and the number of tube transfers and freeze-thaw cycles, because these aspects of the procedure have been shown to affect AD biomarker measurements. A survey of the impact of several individual preanalytical procedures on the measurement of AD biomarkers in CSF was conducted for this review article, and the implications of the differences among them are discussed. Furthermore, following a review of the procedures used in Korean and international biomarker laboratories, a consensus was reached among a cooperative Korean multicenter research group regarding a standardized protocol for the analysis of AD biomarkers in CSF. All efforts were made to be stringent regarding the controversial issues associated with this protocol, thus minimizing the confounding influence of various factors on current investigations using established AD biomarkers and on future studies using novel biomarkers of AD and other neurodegenerative disorders.     

Diagnosis and management of Alzheimer's disease

The diagnosis of Alzheimer's disease (AD) is a 2-stage process, in stage 1, the dementia syndrome, comprising neuropsychologic and neuropsychiatrie components together with deficits in activities of daily living, is differentiated on clinical grounds from a number of other conditions (delirium, concomitant physical illness, drug treatment normal memory loss, etc), in stage 2, the cause is determined, AD being the most common, followed by vascular dementia, Lewy-body dementia, frontal lobe dementia, and a host of so-called secondary causes. Although a mixed Alzheimer/vascular picture is common, gradual onset of multiple cognitive deficits is typical of AD, while abrupt onset, a fluctuating course, hypertension, and focal neurologic signs suggest vascular dementia, in Lewy-body dementia, memory loss may not be an early feature, and fluctuation can be marked by distressing psychotic symptoms and behavioral disturbance, investigations should be minimally invasive and relatively cheap, confined to routine blood tests, chest x-ray and/or electrocardiogram if clinically indicated, cardiologie or neurologic referral in the presence of cerebrovascular signs, and computed tomography if an intracranial lesion is suspected. Accurate diagnosis enables the clinician to outline the disease course to the family and inform them of genetic implications. Numerous instruments for assessing cognitive function, global status, psychiatric well-being, and activities of daily living are briefly reviewed.     

Multiplex Analysis of Cytokines in the Serum and Cerebrospinal Fluid of Patients With Alzheimer's Disease by Color-Coded Bead Technology

Background and purpose

The availability and promise of effective treatments for neurodegenerative disorders are increasing the importance of early diagnosis. Having molecular and biochemical markers of Alzheimer''s disease (AD) would complement clinical approaches, and further the goals of early and accurate diagnosis. Combining multiple biomarkers in evaluations significantly increases the sensitivity and specificity of the biochemical tests.

Methods

In this study, we used color-coded bead-based Luminex technology to test the potential of using chemokines and cytokines as biochemical markers of AD. We measured the levels of 22 chemokines and cytokines in the serum and cerebrospinal fluid (CSF) of 32 de novo patients (13 controls, 11 AD, and 8 Parkinson''s disease [PD]).

Results

MCP-1 was the only cytokine detectable in CSF, and its levels did not differ between control and disease groups. However, the serum concentration of eotaxin was significantly higher in AD patients than in the control group.

Conclusions

The analysis of multiple inflammatory mediators revealed marginal differences in their CSF and serum concentrations for the differential diagnosis of AD and PD. These results provide evidence that immunological responses are not major contributors to the pathogenesis of AD and PD.     

An overview of circulating cell-free microRNAs as putative biomarkers in Alzheimer's and Parkinson's Diseases

Circulating cell-free microRNAs (miRNAs) are stable in many biological fluids and their expression profiles can suffer changes under different physiological and pathological conditions. In the last few years, miRNAs have been proposed as putative noninvasive biomarkers in diagnosis, prognosis and response to treatment for several diseases, including neurodegenerative disorders as Alzheimer's disease (AD) and Parkinson's disease (PD). Cognitive and/or motor impairments are usually considered for establishing clinical diagnosis, and at this stage, the majority of the neurons may already be lost making difficult attempts of novel therapies. In this review, we intend to survey the circulating cell-free miRNAs found as dysregulated in cerebrospinal fluid, serum and plasma samples in AD and PD patients, and show how those miRNAs can be useful for early and differential diagnosis. Beyond that, we highlighted the miRNAs that are possibly related to common molecular mechanisms in the neurodegeneration process, as well those miRNAs related to specific disease pathways.     

早发性与晚发性阿尔茨海默病的多模态影像学研究进展

阿尔茨海默病（AD）是最常见的神经系统退行性疾病,其特征是以记忆为主的进行性认知功能损害。根据发病年龄可分为早发性AD（EOAD）和晚发性AD（LOAD）,二者在临床进程和神经病理学方面存在差异。近年来,多种影像学技术和新型示踪剂的开发促进了AD影像学生物标志物的出现,为深入了解EOAD和LOAD的影像学特征提供了依据。该文旨在对EOAD和LOAD的磁共振成像、单光子发射计算机断层扫描、正电子发射断层扫描的多模态影像学研究进展进行总结,探讨两种类型AD的影像学特征与区别。     

NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.     

The epigenetic dimension of Alzheimer's disease: causal,consequence, or curiosity?

Early-onset, familial Alzheimer''s disease (AD) is rare and may be attributed to disease-causinq mutations. By contrast, late onset, sporadic (non-Mendelian) AD is far more prevalent and reflects the interaction of multiple genetic and environmental risk factors, together with the disruption of epigenetic mechanisms controlling gene expression. Accordingly, abnormal patterns of histone acetylation and methylation, as well as anomalies in global and promoter-specific DNA methylation, have been documented in AD patients, together with a deregulation of noncoding RNA. In transgenic mouse models for AD, epigenetic dysfunction is likewise apparent in cerebral tissue, and it has been directly linked to cognitive and behavioral deficits in functional studies. Importantly, epigenetic deregulation interfaces with core pathophysiological processes underlying AD: excess production of Aβ42, aberrant post-translational modification of tau, deficient neurotoxic protein clearance, axonal-synaptic dysfunction, mitochondrial-dependent apoptosis, and cell cycle re-entry. Reciprocally, DNA methylation, histone marks and the levels of diverse species of microRNA are modulated by Aβ42, oxidative stress and neuroinflammation. In conclusion, epigenetic mechanisms are broadly deregulated in AD mainly upstream, but also downstream, of key pathophysiological processes. While some epigenetic shifts oppose the evolution of AD, most appear to drive its progression. Epigenetic changes are of irrefutable importance for AD, but they await further elucidation from the perspectives of pathogenesis, biomarkers and potential treatment.     

Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP)

Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer''s disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11 840 cases, 10 931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on γ-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P⩽0.0006). SORCS3, but not SORCS2 or SORT1, showed reduced expression in AD compared with control brains, but knockdown of all the three genes using short hairpin RNAs in HEK293 cells caused a significant threefold increase in APP processing (from P<0.001 to P<0.05). These findings indicate that in addition to SORL1 and SORCS1, variants in other members of the VPS10 domain receptor family (that is, SORCS1, SORCS2, SORCS3) are associated with AD risk and alter APP processing. More importantly, the results indicate that variants within these genes have epistatic effects on AD risk.     

Is there a neuropathology difference between mild cognitive impairment and dementia?

The number of studies that have investigated the neuropathology of mild cognitive impairment (MCI) is small, but growing. In this paper we have restricted our focus to the consideration of the presence and extent of postmortem findings relevant to the neuropathology of Alzheimer''s disease. We have drawn from studies that have investigated the postmortem neurobiology of the brains of persons with cognitive function at the interface between unimpaired normal function and mild but definite dementia. The data derived from these studies suggest that i) the brains of persons with MCI evidence significant neuropathological and neurobiological changes relative to those without coqnitive impairment; ii) in general, the neuropathological and neurobiological changes are qualitatively similar to those observed in the brains of persons with frank AD-like dementia; and iii) the neuropathological and neurobiological brain changes associated with MCI are quantitatively less than those of persons who meet criteria for dementia. Thus, the available, albeit limited, data suggests that MCI is associated with the early stages of the neurobiological and neuropathological changes that culminate in the florid lesions of AD; including the accumulation of neuritic plaques, neurofibrillary tangles, synaptic and neurotransmitter associated deficits, and significant neuronal cell death.