The discovery and early validation of novel plasma biomarkers in mild-to-moderate Alzheimer's disease patients responding to treatment with rosiglitazone

Recent advances in clinical, pathological and neuroscience studies have identified disease-modifying therapeutic approaches for Alzheimer's disease that are now in clinical trials. This has highlighted the need for reliable and convenient biomarkers for both early disease diagnosis and a rapid signal of drug efficacy. We describe the identification and assessment of a number of candidate biomarkers in patients with Alzheimer's disease and the correlation of those biomarkers with rosiglitazone therapeutic efficacy, as represented by a change in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). Plasma from 41 patients with Alzheimer's disease were analysed by open platform proteomics at baseline and after receiving 8 mg rosiglitazone for 24 weeks. From a comparison of protein expression following treatment with rosiglitazone, 97 proteins were observed to be differentially expressed with a p-value<0.01. From this analysis and comparison to recently published data from our laboratory, a prioritized list of 10 proteins were analysed by immunoassay and/or functional assay in a wider set of samples from the same clinical study, representing a rosiglitazone dose response, in order to verify the changes observed. A number of these proteins appeared to show a correlation with change in ADAS-Cog at the higher treatment doses compared with the placebo. Alpha-2-macroglobulin, complement C1 inhibitor, complement factor H and apolipoprotein E expression showed a correlation with ADAS-Cog score at the higher doses (4 mg and 8 mg). These results are discussed in light of the pathology and other recently published data.     

华生关怀理论对老年痴呆症患者的临床干预效果

目的:探索华生关怀理论在老年痴呆症患者临床护理中的应用效果,为临床护理提供参考。方法:选择2012年3月至2014年3月我院收治的老年痴呆患者200例,随机分为治疗组和对照组。对照组采用常规护理措施,治疗组采用华生关怀理论进行干预。分别于干预前后采用简易智能量表(MMSE)、蒙特利尔认知评估量表(MOCA)、AD评定量表认知部分(ADAS-Cog)、日常生活活动量表(ADL)、中医症状积分量表对两组患者进行测评。结果:与干预前比较,两组患者干预后的MMSE和MOCA评分显著升高,ADAS-Cog、ADL和中医症状积分明显降低,差异具有统计学意义(P0.05);与对照组比较,治疗组患者变化更明显(P0.01)。两组患者干预前后的血尿常规、肝肾功能及心电图等指标无显著差异(P0.05)。结论:利用华生关怀理论护理老年痴呆症患者,不仅能改善患者的病情,缓解心理压力,而且有利于减轻家庭和社会负担。     

The "Alzheimer's disease signature": potential perspectives for novel biomarkers

Alzheimer's disease is a progressive and neurodegenerative disorder which involves multiple molecular mechanisms. Intense research during the last years has accumulated a large body of data and the search for sensitive and specific biomarkers has undergone a rapid evolution. However, the diagnosis remains problematic and the current tests do not accurately detect the process leading to neurodegeneration. Biomarkers discovery and validation are considered the key aspects to support clinical diagnosis and provide discriminatory power between different stages of the disorder. A considerable challenge is to integrate different types of data from new potent approach to reach a common interpretation and replicate the findings across studies and populations. Furthermore, long-term clinical follow-up and combined analysis of several biomarkers are among the most promising perspectives to diagnose and manage the disease. The present review will focus on the recent published data providing an updated overview of the main achievements in the genetic and biochemical research of the Alzheimer's disease. We also discuss the latest and most significant results that will help to define a specific disease signature whose validity might be clinically relevant for future AD diagnosis.     

L’imagerie TEP-traceurs des plaques amyloïdes : le point de vue du clinicien

The purpose of this article is to summarize the main elements of clinician point of view concerning the contribution of amyloid neuroimaging in the diagnostic approach of the Alzheimer's disease. The main pathological characteristics of the Alzheimer's disease are established by two types of protein aggregates: the extracellular plaques (containing Aβ aggregates) and neurofibrillary tangles (composed of aggregates of tau-protein). At present, the use of biomarkers is more and more included in the diagnostic approach of Alzheimer's disease. The possibility to highlight in vivo cortical amyloid deposits through the amyloid neuroimaging can allow the realization of an earlier diagnosis. However, the amyloid imaging is a “physiopathological” biomarker and is not correlated with the clinical evaluation. It is still difficult to differentiate the Alzheimer's disease of the other neurodegenerative diseases.     

La enfermedad de Alzheimer antes de la demencia. Beneficios del diagnóstico precoz

Given population aging and the rise in the number of persons with Alzheimer's disease, measures that aim not only to delay but also to prevent the development of this disease are increasingly required. Advances in the diagnosis of Alzheimer's disease support the need for a review of current clinical standards for mildcognitive impairment and provide new goals in the early treatment of this disease. The current diagnostic process should be refocussed toward the pathological substrate of this disease rather than symptoms in order to initiate therapeutic measures as soon as possible without waiting for clinical manifestations to appear. Such an approach is essential in patients with greater cognitive reserve, in whom the lesions are usually more severe at diagnosis and treatment is less effective.To identify disease-modifying therapies to delay the onset of the clinical symptoms of Alzheimer's disease in cognitively intact persons at high risk, biomarkers for this disease must be validated. A single biomarker is unlikely to provide the required diagnostic accuracy and therefore a multimodal approach, incorporating biochemical, neuropathological and anatomical and metabolic neuroimaging methods, should be employed. To optimize the results of drugs under investigation, a combination of biomarkers should be used to select appropriate participants in the earliest phases of the disease, and disease progression should be followedup.Early diagnosis might clarify essential questions in the care of patients with Alzheimer's disease, such as the possibility of distinguishing among various subtypes, thus encouraging the development of optimal treatments for each.The ultimate goal is to develop disease-modifying treatments that could be initiated early, while patients are asymptomatic or only minimally symptomatic, to maintain their quality of life.     

To be at the right place at the right time

Diagnosing Alzheimer's disease through MRI neuroimaging biomarkers has been used as a complementary marker for traditional clinical markers to improve diagnostic accuracy and also help in developing new pharmacotherapeutic trials. It has been revealed that longitudinal analysis of the whole brain atrophy has the power of discriminating Alzheimer's disease and elderly normal controls. In this work, effect of involving intermediate atrophy rates and impact of using uncorrelated principal components of these features instead of original ones on discriminating normal controls and Alzheimer's disease subjects, is inspected. In fact, linear discriminative analysis of atrophy rates is used to classify subjects into Alzheimer's disease and controls. Leave-one-out cross-validation has been adopted to evaluate the generalization rate of the classifier along with its memorization. Results show that incorporating uncorrelated version of intermediate features leads to the same memorization performance as the original ones but higher generalization rate. As a conclusion, it is revealed that in a longitudinal study, using intermediate MRI scans and transferring them to an uncorrelated feature space can improve diagnostic accuracy.     

Luteinizing hormone as a key player in the cognitive decline of Alzheimer's disease

This article is part of a Special Issue "SBN 2014".Alzheimer's disease is one of the most prevalent and costly neurological diseases in the world. Although decades of research have focused on understanding Alzheimer's disease pathology and progression, there is still a great lack of clinical treatments for those who suffer from it. One of the factors most commonly associated with the onset of Alzheimer's disease is a decrease in levels of gonadal hormones, such as estrogens and androgens. Despite the correlational and experimental data which support the role of these hormones in the etiology of Alzheimer's disease, clinical trials involving their reintroduction through hormone therapy have had varied results and these gonadal hormones often have accompanying health risks. More recently, investigation has turned toward other hormones in the hypothalamic–pituitary–gonadal axis that are disrupted by age-related decreases in gonadal hormones. Specifically, luteinizing hormone, which is increased with age in both men and women (in response to removal of negative feedback), has surfaced as a potentially powerful player in the risk and onset of Alzheimer's disease. Mounting evidence in basic research and epidemiological studies supports the role of elevated luteinizing hormone in exacerbating age-related cognitive decline in both males and females. This review summarizes the recent developments involving luteinizing hormone in increasing the cognitive deficits and molecular pathology characteristic of Alzheimer's disease.     

Genética y enfermedad de Alzheimer: población en riesgo

The high prevalence of Alzheimer's disease, along with the possibility of new approaches in diagnosis through the use of biomarkers of cerebrospinal fluid is shifting the focus to the elderly with dementia or at risk. In this sense it seems important to review the genetic aspects of the elderly with familial Alzheimer's disease as well as those at risk. The wide distribution of genetic studies associated with this condition may also be helpful. To the classical findings of the genes for amyloid, the presenilins and apolipoprotein E, we must add other genes recently implicated in the pathogenesis of the disease, among which are found the clusterin gene, encoding the phosphatidyl-inositol-binding clathrin assembly protein gene, and the receptor for the complement C3b protein.     

Gray and White Matter Changes in Subjective Cognitive Impairment,Amnestic Mild Cognitive Impairment and Alzheimer's Disease: A Voxel-Based Analysis Study

Subjective cognitive impairment may be a very early at-risk period of the continuum of dementia. However, it is difficult to discriminate at-risk states from normal aging. Thus, detection of the early pathological changes in the subjective cognitive impairment period is needed. To elucidate these changes, we employed diffusion tensor imaging and volumetry analysis, and compared subjective cognitive impairment with normal, mild cognitive impairment and Alzheimer''s disease. The subjects in this study were 39 Alzheimer''s disease, 43 mild cognitive impairment, 28 subjective cognitive impairment and 41 normal controls. There were no statistically significant differences between the normal control and subjective cognitive impairment groups in all measures. Alzheimer''s disease and mild cognitive impairment had the same extent of brain atrophy and diffusion changes. These results are consistent with the hypothetical model of the dynamic biomarkers of Alzheimer''s disease.     

Analysis of lipophilic fluorescent products in blood of Alzheimer's disease patients

Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by cognitive decline. Prodromal stage of AD, also called mild cognitive impairment (MCI), especially its amnestic type (aMCI), precedes dementia stage of AD. There are currently no reliable diagnostic biomarkers of AD in the blood. Alzheimer's disease is accompanied by increased oxidative stress in brain, which leads to oxidative damage and accumulation of free radical reaction end‐products. In our study, specific products of lipid peroxidation in the blood of AD patients were studied. Lipophilic extracts of erythrocytes (AD dementia = 19, aMCI = 27, controls = 16) and plasma (AD dementia = 11, aMCI = 17, controls = 16) were analysed by fluorescence spectroscopy. The level of these products is significantly increased in erythrocytes and plasma of AD dementia and aMCI patients versus controls. We concluded that oxidative stress end‐products are promising new biomarkers of AD, but further detailed characterisation of these products is needed.     

A Patient with Posterior Cortical Atrophy Possesses a Novel Mutation in the Presenilin 1 Gene

Posterior cortical atrophy is a dementia syndrome with symptoms of cortical visual dysfunction, associated with amyloid plaques and neurofibrillary tangles predominantly affecting visual association cortex. Most patients diagnosed with posterior cortical atrophy will finally develop a typical Alzheimer''s disease. However, there are a variety of neuropathological processes, which could lead towards a clinical presentation of posterior cortical atrophy. Mutations in the presenilin 1 gene, affecting the function of γ-secretase, are the most common genetic cause of familial, early-onset Alzheimer''s disease. Here we present a patient with a clinical diagnosis of posterior cortical atrophy who harbors a novel Presenilin 1 mutation (I211M). In silico analysis predicts that the mutation could influence the interaction between presenilin 1 and presenilin1 enhancer-2 protein, a protein partner within the γ-secretase complex. These findings along with published literature support the inclusion of posterior cortical atrophy on the Alzheimer''s disease spectrum.     

Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group

ObjectiveTo evaluate the efficacy and safety of galantamine in the treatment of Alzheimer''s disease.DesignRandomised, double blind, parallel group, placebo controlled trial.Setting86 outpatient clinics in Europe and Canada.Participants653 patients with mild to moderate Alzheimer''s disease.InterventionPatients randomly assigned to galantamine had their daily dose escalated over three to four weeks to maintenance doses of 24 or 32 mg.ResultsAt six months, patients who received galantamine had a significantly better outcome on the 11 item cognitive subscale of the Alzheimer''s disease assessment scale than patients in the placebo group (mean treatment effect 2.9 points for lower dose and 3.1 for higher dose, intention to treat analysis, P<0.001 for both doses). Galantamine was more effective than placebo on the clinician''s interview based impression of change plus caregiver input (P<0.05 for both doses v placebo). At six months, patients in the higher dose galantamine group had significantly better scores on the disability assessment for dementia scale than patients in the placebo group (mean treatment effect 3.4 points, P<0.05). Apolipoprotein E genotype had no effect on the efficacy of galantamine. 80% (525) of patients completed the study.ConclusionGalantamine is effective and well tolerated in Alzheimer''s disease. As galantamine slowed the decline of functional ability as well as cognition, its effects are likely to be clinically relevant.     

The basics of preclinical drug development for neurodegenerative disease indications

Background

Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients.

Methods

In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPα and sAPPβ), amyloid beta fragment 1-42 (Aβ_1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease.

Results

CSF sAPPα and sAPPβ concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Aβ_1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections.

Conclusions

Parallel reductions of CSF sAPPα and sAPPβ in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.     

Effects of Gingko biloba supplementation in Alzheimer's disease patients receiving cholinesterase inhibitors: Data from the ICTUS study

Ginkgo biloba (Gb) is currently the most investigated and adopted herbal remedy for cognitive disorders and Alzheimer's disease (AD). Nevertheless, its efficacy in the prevention and treatment of dementia still remains controversial. Specifically, the added effects of Gb in subjects already receiving “conventional” anti-dementia treatments have been to date very scarcely investigated. We evaluated whether the use of Gb is associated with additional cognitive and functional benefit in AD patients already in treatment with cholinesterase inhibitors (ChEIs).Data are from mild to moderate AD patients under ChEI treatment recruited in the Impact of Cholinergic Treatment USe (ICTUS) study. Mixed model analyses were performed to measure six-monthly modifications in the Mini Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score, and the Activities of Daily Living (ADL) scale over a follow-up of 1 year according to the additional Gb supplementation.A total of 828 subjects were considered for the present analyses. Significantly different modifications at the MMSE score over the 12-month follow-up were reported between patients on combined therapy compared to those only taking ChEIs. On the contrary, the modification of the ADAS-Cog score between the two groups did not show statistically significant differences, although similar trends were noticed. No significant modifications of the two adopted outcome measures were observed at the mid-term 6-month evaluation. The modifications over time of the ADL score did not show statistically significant differences between the two groups of interest.Our findings suggest that Gb may provide some added cognitive benefits in AD patients already under ChEIs treatment. The clinical meaningfulness of such effects remains to be confirmed and clarified.     

Efficacy and Safety of A Liposome-Based Vaccine against Protein Tau,Assessed in Tau.P301L Mice That Model Tauopathy

Progressive aggregation of protein Tau into oligomers and fibrils correlates with cognitive decline and synaptic dysfunction, leading to neurodegeneration in vulnerable brain regions in Alzheimer''s disease. The unmet need of effective therapy for Alzheimer''s disease, combined with problematic pharmacological approaches, led the field to explore immunotherapy, first against amyloid peptides and recently against protein Tau. Here we adapted the liposome-based amyloid vaccine that proved safe and efficacious, and incorporated a synthetic phosphorylated peptide to mimic the important phospho-epitope of protein Tau at residues pS396/pS404. We demonstrate that the liposome-based vaccine elicited, rapidly and robustly, specific antisera in wild-type mice and in Tau.P301L mice. Long-term vaccination proved to be safe, because it improved the clinical condition and reduced indices of tauopathy in the brain of the Tau.P301L mice, while no signs of neuro-inflammation or other adverse neurological effects were observed. The data corroborate the hypothesis that liposomes carrying phosphorylated peptides of protein Tau have considerable potential as safe and effective treatment against tauopathies, including Alzheimer''s disease.     

Emerging evidence implicating a role for neurexins in neurodegenerative and neuropsychiatric disorders

Synaptopathies are brain disorders characterized by dysfunctional synapses, which are specialized junctions between neurons that are essential for the transmission of information. Synaptic dysfunction can occur due to mutations that alter the structure and function of synaptic components or abnormal expression levels of a synaptic protein. One class of synaptic proteins that are essential to their biology are cell adhesion proteins that connect the pre- and post-synaptic compartments. Neurexins are one type of synaptic cell adhesion molecule that have, recently, gained more pathological interest. Variants in both neurexins and their common binding partners, neuroligins, have been associated with several neuropsychiatric disorders. In this review, we summarize some of the key physiological functions of the neurexin protein family and the protein networks they are involved in. Furthermore, examination of published literature has implicated neurexins in both neuropsychiatric and neurodegenerative disorders. There is a clear link between neurexins and neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia. However, multiple expression studies have also shown changes in neurexin expression in several neurodegenerative disorders, including Alzheimer''s disease and Parkinson''s disease. Therefore, this review highlights the potential importance of neurexins in brain disorders and the importance of doing more targeted studies on these genes and proteins.     

The role of lysosomal cathepsins in neurodegeneration: Mechanistic insights,diagnostic potential and therapeutic approaches

Lysosomes are ubiquitous organelles with a fundamental role in maintaining cellular homeostasis by mediating degradation and recycling processes. Cathepsins are the most abundant lysosomal hydrolyses and are responsible for the bulk degradation of various substrates. A correct autophagic function is essential for neuronal survival, as most neurons are post-mitotic and thus susceptible to accumulate cellular components. Increasing evidence suggests a crucial role of the lysosome in neurodegeneration as a key regulator of aggregation-prone and disease-associated proteins, such as α-synuclein, β-amyloid and huntingtin. Particularly, alterations in lysosomal cathepsins CTSD, CTSB and CTSL can contribute to the pathogenesis of neurodegenerative diseases as seen for neuronal ceroid lipofuscinosis, synucleinopathies (Parkinson's disease, Dementia with Lewy Body and Multiple System Atrophy) as well as Alzheimer's and Huntington's disease. In this review, we provide an overview of recent evidence implicating CTSD, CTSB and CTSL in neurodegeneration, with a special focus on the role of these enzymes in α-synuclein metabolism. In addition, we summarize the potential role of lysosomal cathepsins as clinical biomarkers in neurodegenerative diseases and discuss potential therapeutic approaches by targeting lysosomal function.     

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin–proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid‐β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD‐like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.     

MicroRNAs circulate around Alzheimer's disease

A select group of microRNAs identified in blood samples can differentiate between Alzheimer''s disease, other neurological disorders and age-matched healthy controls with high accuracy.Please see related Research article, http://genomebiology.com/2013/14/7/R78Millions of people suffer from Alzheimer''s disease (AD) every year, and the number of afflicted individuals is expected to increase drastically worldwide as the elderly population expands. AD is the most common form of dementia and often onsets after age 65. Currently, analysis of cerebrospinal fluid proteins, such as Aβ42, tau and p-tau, can only truly indicate a confirmation of AD diagnosis based on a clinical suspicion, or as a differential diagnosis from other neurological diseases that cause dementia-like symptoms. Thus, the search to find early-stage biomarkers of this disease is of utmost importance.Recently, blood-based biomarkers for AD have been proposed as attractive diagnostic tools, as they are non-invasive, highly specific and sensitive, and can be isolated with standard laboratory equipment. A number of studies have identified such blood-based AD biomarkers and demonstrated promising results. For example, one study reported a panel of three blood markers (cortisol, von Willebrand factor and oxidized low-density lipoprotein antibodies) that distinguished AD patients from healthy controls [1], while another group identified 18 proteins in blood plasma that could differentiate AD patients from controls with clinically relevant accuracy, sensitivity and specificity [2].     

Evaluation of the relationship among gene expressions and enzyme activities with antioxidant role and presenilin 1 expression in Alzheimer's disease

It is known that oxidative stress originating from reactive oxygen species plays a role in the pathogenesis of Alzheimer's disease. In this study, the role of antioxidant status associated with oxidative stress in Alzheimer's disease was investigated. Peripheral blood samples were obtained from 28 healthy individuals (as control) and 28 Alzheimer's patients who met the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria. Catalase, glutathione S-transferase and paraoxonase 1 enzyme activities in blood plasma and glutathione S-transferase enzyme activities in erythrocytes were determined by spectrophotometer. Catalase, glutathione S-transferase and presenilin 1 gene expressions in leukocytes were determined using qRT-PCR. Data were analysed with SPSS one-way anova , a LSD post hoc test at p < 0.05. The activity of each enzyme was significantly reduced in Alzheimer's patients compared to control. The catalase gene expression level did not change compared to the control. Glutathione S-transferase and presenilin 1 gene expression levels were increased compared to the control.