Different Stages Of Alzheimer's Disease Research Articles

An investigation of affective theory of mind ability and its relation to neuropsychological functions in Alzheimer's disease.

Although cognitive theory of mind (ToM) has been largely studied within neurodegenerative disorders including Alzheimer's disease (AD), studies focusing on affective ToM are relatively limited, yielding inconsistent findings. The current study aimed at investigating affective ToM abilities within different stages of AD (mild AD dementia [ADD], mild cognitive impairment [MCI], and subjective cognitive impairment [SCI]), together with its relationship with neuropsychological functioning. Eighty-one participants were tested with two different ToM tasks (Faux Pas Recognition Test [FPR] and Reading Mind in the Eyes Test [RMET]) and tests of attention, executive functions, episodic memory, and facial recognition. Our results showed two different affective ToM profiles in AD continuum: while ADD group performed poorly on both tasks of ToM, MCI group displayed deteriorated performance on RMET but not on FPR. In addition, ToM performance was significantly related to episodic memory and verbal fluency within the overall sample. These findings suggest that impairment in the decoding process of emotional cues could begin even in the prodromal stage of AD. In contrast, the reasoning process of emotional information, as measured with FPR, could be preserved until the dementia stage. Moreover, the relation of affective ToM with amnestic functions and verbal abilities could provide evidence of a domain-general ToM impairment in AD.

Exercise-Induced Cognitive Improvement Is Associated with Sodium Channel-Mediated Excitability in APP/PS1 Mice.

Elevated brain activation, or hyperexcitability, induces cognitive impairment and confers an increased risk of Alzheimer's disease (AD). Blocking the overexcitation of the neural network may be a promising new strategy to prevent, halt, and even reverse this condition. Physical exercise has been shown to be an effective cognitive enhancer that reduces the risk of AD in elderly individuals, but the underlying mechanisms are far from being fully understood. We explored whether long-term treadmill exercise attenuates amyloid precursor protein (APP)/presenilin-1 (PS1) mutation-induced aberrant network activity and thus improves cognition by altering the numbers and/or distribution of voltage-gated sodium channels (Nav) in transgenic mice. APP/PS1 mice aged 2, 3.5, 5, 6.5, 8, and 9 months underwent treadmill exercise with different durations or at different stages of AD. The alterations in memory, electroencephalogram (EEG) recordings, and expression levels and distributions of Nav functional members (Nav1.1α, Nav1.2, Nav1.6, and Navβ2) were evaluated. The results revealed that treadmill exercise with 12- and 24-week durations 1) induced significant improvement in novel object recognition (NOR) memory and Morris water maze (MWM) spatial memory; 2) partially reduced abnormal spike activity; and 3) redressed the disturbed cellular distribution of Nav1.1α, aberrant Navβ2 cleavage augmentation, and Nav1.6 upregulation. Additionally, APP/PS1 mice in the 24-week exercise group showed better performance in the NOR task and a large decrease in Nav1.6 expression, which was close to the wild-type level. This study suggests that exercise improves cognition and neural activity by altering the numbers and distribution of hippocampal Nav in APP/PS1 mice. Long-term treadmill exercise, for about 24 weeks, starting in the preclinical stage, is a promising therapeutic strategy for preventing AD and halting its progress.

Amyloid-beta peptide detection via aptamer-functionalized nanowire sensors exploiting single-trap phenomena

New highly sensitive direct methods for the early detection of peptides involved in Alzheimer's disease (AD) are required in order to prolong effective and healthy memory and thinking capabilities and also to stop the factors resulting in AD. In this contribution, we report the successful demonstration of a label-free approach for the detection of amyloid-beta (Aβ) peptides by highly selective aptamers immobilized onto the SiO2 surface of the fabricated sensors. A modified single-stranded deoxyribonucleic acid (ssDNA) aptamer was specially designed and synthesized to detect the target amyloid beta-40 sequence (Aβ-40). Electrolyte–insulator–semiconductor (EIS) structures as well as silicon (Si) nanowire (NW) field-effect transistors (FETs) covered with a thin SiO2 dielectric layer have been successfully functionalized with Aβ-40-specific aptamers and used to detect ultra-low concentrations of the target peptide. The binding of amyloid-beta peptides of different concentrations to the surface of the sensors varied in the range from 0.1 pg/ml to 10 μg/ml resulting in a change of the surface potential was registered by the fabricated devices. Moreover, we show that the single-trap phenomena observed in the novel Si two-layer (TL) NW FET structures with advanced characteristic parameters can be effectively used to increase the sensitivity of nanoscale sensors. The obtained experimental data demonstrate a highly sensitive and reliable detection of ultra-low concentrations of the Aβ-40 peptides. This opens up prospects for the development of real-time electrical biosensors for studying and understanding different stages of AD by utilizing Si TL NW FET structures fabricated on the basis of cost-efficient CMOS-compatible technology.

Chemokine profile in Alzheimer’s disease: Results from a Mexican population

Alzheimer’s Disease (AD) is the main cause of dementia worldwide. Inflammatory cytokines and chemokines are related to different stages of AD and may be related to the progression of the disease. A Case-control study of AD patients healthy, age and sex-matched controls was carried out at the University Hospital “Dr. José E. Gonzalez”, UANL. Cytokines and chemokines were measured from blood samples taken from the cubital vein after 8 h of fast. We included 78 subjects from which 29 had AD and 49 were healthy controls. CTACK (p = 0.003), MIG (p = 0.043) and SDF-1α (p = 0.001) were increased in subjects with AD, whereas no change was observed in other cytokines and chemokines. CTACK, MIG and SDF-1α are present in the Central Nervous System and are related to inflammation and endothelial dysfunction. Longitudinal studies evaluating the change of these chemokines in AD are needed to understand their role in AD progression and possibly lead to new diagnostic and therapeutic targets.

A Gaussian-based model for early detection of mild cognitive impairment using multimodal neuroimaging

BackgroundDiagnosis of early mild cognitive impairment (EMCI) as a prodromal stage of Alzheimer’s disease (AD) with its delineation from the cognitively normal (CN) group remains a challenging but essential step for the planning of early treatment. Although several studies have focused on the MCI diagnosis, this study introduces the early stage of MCI to assess more thoroughly the earliest signs of disease manifestation and progression. New methodWe used random forest feature selection model with a Gaussian-based algorithm to perform method evaluation. This integrated method serves to define multivariate normal distributions in order to classify different stages of AD, with the focus placed on detecting EMCI subjects in the most challenging classification of CN vs. EMCI. ResultsUsing 896 participants classified into the four categories of CN, EMCI, late mild cognitive impairment (LMCI) and AD, the results show that the EMCI group can be delineated from the CN group with a relatively high accuracy of 78.8% and sensitivity of 81.3%. Comparison with existing method(s)The feature selection model and classifier are compared with some other prominent algorithms. Although higher accuracy has been achieved using the Gaussian process (GP) model (78.8%) over the SVM classifier (75.6%) for CN vs. EMCI classification, with 0.05 being the cutoff for significance, and based on student’s t-test, it was determined that the differences for accuracy, sensitivity, specificity between the GP method and support vector machine (SVM) are not statistically significant. ConclusionAddressing the challenging classification of CN vs. EMCI provides useful information to help clinicians and researchers determine essential measures that can help in the early detection of AD.

The application of weighted gene co-expression network analysis in identifying key modules and hub genes associated with disease status in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative condition that affects more than 15 million individuals globally. However, a predictive molecular biomarker to distinguish the different stages of AD patients is still lacking. A weighted gene co-expression network analysis (WGCNA) was employed to systematically identify the co-expressed gene modules and hub genes connected with AD development based on a microarray dataset (GSE1297) from the Gene Expression Omnibus (GEO) database. An independent validation cohort, GSE28146, was utilized to assess the diagnostic efficiency for distinguishing the different stages of AD. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and western blotting analysis were applied to examine the mRNA and protein level of GRIK1, respectively, in AD mice established with the expression of mutant amyloid precursor protein and wild type mice. The morphology of neurons was investigated using phalloidin staining. We identified 16 co-expressed genes modules, with the pink module showing significant association with all three disease statuses [neurofibrillary tangle (NFT), BRAAK, and mini-mental state examination (MMSE)]. Enrichment analysis specified that these modules were enriched in phosphatidylinositol 3-kinase (PI3K) signaling and ion transmembrane transport. The validation cohort GSE28146 confirmed that six hub genes in the pink module could distinguish severe and non-severe AD patients [area under the curve (AUC) >0.7]. These hub genes might act as a biomarker and help to differentiate diverse pathological stages for AD patients. Finally, one of the hubs, GRIK1, was validated by an animal AD model. The mRNA and protein level of GRIK1 in the AD hippocampus was increased compared with the control group (NC) hippocampus. Phalloidin staining showed that dendritic length of the GRIK1 pCDNA3.1 group was shorter than that of the NC group. In summary, we systematically recognized co-expressed gene modules and genes related to AD stages, which gave insight into the fundamental mechanisms of AD progression and revealed some probable targets for the treatment of AD.

Transcriptomic and Network Analysis Highlight the Association of Diabetes at Different Stages of Alzheimer's Disease.

Alzheimer’s disease (AD) and type 2 diabetes (T2D) are among the most prevalent chronic diseases affecting the aging population. Extensive research evidence indicates that T2D is a well-established risk factor for AD; however, the molecular mechanisms underlying this association have not been fully elucidated. Furthermore, how T2D may contribute to the progression of AD is a subject of extensive investigation. In this study, we compared the blood transcriptome of patients with mild cognitive impairment (MCI), AD, and advanced AD to those afflicted with T2D to unveil shared and unique pathways and potential therapeutic targets. Blood transcriptomic analyses revealed a positive correlation between gene expression profiles of MCI, AD, and T2D in seven independent microarrays. Interestingly, gene expression profiles from women with advanced AD correlated negatively with T2D, suggesting sex-specific differences in T2D as a risk factor for AD. Network and pathway analysis revealed that shared molecular networks between MCI and T2D were predominantly enriched in inflammation and infectious diseases whereas those networks shared between overt AD and T2D were involved in the phosphatidylinositol 3-kinase and protein kinase B/Akt (PI3K-AKT) signaling pathway, a major mediator of insulin signaling in the body. The PI3K-AKT signaling pathway became more significantly dysregulated in the advanced AD and T2D shared network. Furthermore, endocrine resistance and atherosclerosis pathways emerged as dysregulated pathways in the advanced AD and T2D shared network. Interestingly, network analysis of shared differentially expressed genes between children with T2D and MCI subjects identified forkhead box O3 (FOXO3) as a central transcriptional regulator, suggesting that it may be a potential therapeutic target for early intervention in AD. Collectively, these results suggest that T2D may be implicated at different stages of AD through different molecular pathways disrupted during the preclinical phase of AD and more advanced stages of the disease.

Neurogranin as a Cognitive Biomarker in Cerebrospinal Fluid and Blood Exosomes for Alzheimer's Disease and Mild Cognitive Impairment

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with clinical, biological, and pathological features occurring along a continuum from normal to end-stage disease. Currently, the diagnosis of AD depends on clinical assessments and post-mortem neuropathology, which is unbenefited early diagnosis and progressive monitoring. In recent years, clinical studies have reported that the level of cerebrospinal fluid (CSF) and blood neurogranin (Ng) are closely related to the occurrence and subsequent progression of AD. Therefore, the study used meta-analysis to identify the CSF and blood Ng levels for the development of diagnosis biomarker of patients with AD and mild cognitive impairment (MCI). Methods: We did a systematic review and meta-analysis, in which we searched the Pubmed, Embase, Cochrane Library and Web of Science databases from database inception to June 1, 2019, to identify comparative studies to analysis the association of cerebrospinal fluid and blood plasma exosomes Ng with cognitive impairment in patients with AD and MCI. Findings: A total of 24 articles eligible for inclusion and exclusion criteria were assessed, including 4661 individuals, consisting of 1518 AD patients, 1501 MCI patients, and 1642 healthy control subjects. The level of CSF Ng significantly increased in patients with AD and MCI compared with healthy control subjects (SMD: 0.84 [95% CI: 0.70 to 0.98], P<0.001; SMD: 0.53 [95% CI: 0.40 to 0.66], P=0.008), and higher in AD patients than in MCI patients (SMD: 0.18 [95% CI: 0.07 to 0.30], P=0.002), and CSF Ng level of patients with MCI-AD who progressed from MCI to AD was significantly higher than that of patients with stable MCI (sMCI) (SMD: 0.71 [95% CI: 0.25 to 1.16], P=0.002). Moreover, the concentration of Ng in blood plasma exosomes of patients with AD and MCI was lower than that of healthy control subjects (SMD: -6.657 [95% CI: -10.558 to -2.755], P=0.001; and SMD: -3.64 [95% CI: -6.50 to -0.78], P=0.013), and which in patients with AD and MCI-AD were also lower than those in patients with sMCI (P<0.001). Furthermore, regression analysis showed a negative relationship between MMSE scores and CSF Ng levels in MCI patients (slope=-0.249 [95% CI: -0.003 to -0.495], P=0.047). Interpretation: The Ng levels increased in CSF, but decreased in blood plasma exosomes of patients with AD and MCI-AD, and highly associated with cognitive declines. These findings provide the clinical evidence that CSF and blood exosomes Ng can be used as a cognitive biomarker for AD and MCI-AD, and further studies are needed to define the specific range of Ng values for diagnosis at the different stages of AD. Funding Statement: This study was supported by grants from the National Natural Science Foundation of China (grant numbers 81774424 and 81873353). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: The meta-analysis is conducted in strict accordance with the requirements of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement and was registered at International Prospective Register of Systematic Reviews (https://www.crd. york.ac.uk/PROSPERO/) (number CRD42019135344 and CRD42019141393).

Targeting Autophagy for the Treatment of Alzheimer's Disease: Challenges and Opportunities.

Alzheimer’s disease (AD) is the most common type of dementia which characterized by a progressive loss of memory and cognitive function due to degeneration of synapses and axons. Currently, there is no cure for AD. Deposition of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles (NFTs) are two hallmark pathologic changes in the brains of Alzheimer’s patients. Autophagy is the major mechanism in cells responsible for removing protein aggregates. Accumulation of immature autophagic vacuoles (AVs) in dystrophic neurites of Alzheimer patients’ brains suggests that autophagy process is disrupted. Till now, it is far from clear what role autophagy plays in AD, a causative role, a protective role, or just a consequence of the disease process itself. To design more effective therapeutic strategies towards this devastating disorder, it is essential to understand the exact role of autophagy played during different stages of AD.

Semantic inhibition and dementia severity in Alzheimer's disease.

Semantic inhibition is often found to be impaired in Alzheimer´s disease (AD). The sentence completion task (Hayling test) was used to investigate whether it would be useful for differentiating mild AD from moderate AD. Latency responses and error scores in the automatic and inhibition parts of the test were registered in these two groups of patients and in a group of healthy older participants. The types of errors were also analysed. Group differences were analysed by ANOVA. In addition, relationships with other neuropsychological tests were reported. Participants with moderate AD performed worse than controls in both the automatic and inhibition sections, whereas participants with mild AD exhibited impaired performance in the inhibition part, but not in the automatic part. Differences between the groups with mild and moderate AD appeared only in the error scores in the inhibition part, specifically type 3 errors. Error scores in the inhibition part correlated with performance in verbal fluency and working memory tests. The Hayling task may be a useful tool for investigating control of inhibition in different stages of AD because different patterns of responses were observed.

Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer\u2019s disease progression

Soluble aggregates of amyloid-β (Aβ) have been associated with neuronal and synaptic loss in Alzheimer’s disease (AD). However, despite significant recent progress, the mechanisms by which these aggregated species contribute to disease progression are not fully determined. As the analysis of human cerebrospinal fluid (CSF) provides an accessible window into the molecular changes associated with the disease progression, we characterised soluble aggregates present in CSF samples from individuals with AD, mild cognitive impairment (MCI) and healthy controls using a range of sensitive biophysical methods. We used super-resolution imaging and atomic force microscopy to characterise the size and structure of the aggregates present in CSF and correlate this with their ability to permeabilise lipid membranes and induce an inflammatory response. We found that these aggregates are extremely heterogeneous and exist in a range of sizes, varying both structurally and in their mechanisms of toxicity during the disease progression. A higher proportion of small aggregates of Aβ that can cause membrane permeabilization are found in MCI CSF; in established AD, a higher proportion of the aggregates were larger and more prone to elicit a pro-inflammatory response in glial cells, while there was no detectable change in aggregate concentration. These results show that large aggregates, some longer than 100 nm, are present in the CSF of AD patients and suggest that different neurotoxic mechanisms are prevalent at different stages of AD.

NONINVASIVE DETECTION OF AGES ACCUMULATION IN THE EYES’ LENS MAY BE A POWERFUL TECHNIQUE FOR MONITORING ALZHEIMER'S DISEASE

We successfully demonstrated a noninvasive method to measure fluorescence emitted from the eyes lens, showing the fluorescence intensity from diabetic patients was significantly higher than that from normal subjects in chronological age manner1. With advance in electronic technology, we theorize to develop a miniaturized new device for monitoring AGE (advanced glycation end product)-dependent fluorescence for the development of Alzheimer's Disease (AD). Evidences demonstrate AGEs enhance accumulation of amyloid plaques and tau protein in AD. Hyperglycemia-enhanced AGEs result in AD development, via activation of insulin signaling, cerebral glucose dysfunction, oxidative stress, resulting in neuroinflammation and degeneration2-7. Overlapping biological relevance for pathogenesis between AD and diabetes support our hypothesis that detection of AGE-dependent fluorescence in the eyes lens may serve as a biomarker for monitoring AD development. Blue LED source at about 434 nm in the visible region was used to excite specific fluorophors in lens proteins of the human eyes. The light pinpoints exact depths of the lens. Emission of fluorescence at about 490 nm was collected with correction of Rayleigh scattering. With modern information/electronic technology, the normalized fluorescence intensity was processed and digitized, creating a miniaturized device that will have the virtues of noninvasive detection of AGEs in the eyes lens, hand-held, self-scanned, not requiring pupil dilation, and less than 5 second measurement time. We successfully miniaturize a new device for detecting AGE-dependent fluorescence in human eyes lens, which are capable of monitoring AGEs accumulation that reflects the development of AD. The hand-held device is noninvasive, fast, and low cost. The new miniaturized device may be a powerful tool for monitoring the progression of AD in a noninvasive, fast, and inexpensive manner. This unique technology can be of great use in self-referenced detection at different stages of AD and possible early detection of AD so that the disease can be reversed or prevented.

Microglial Trem2 induces synaptic impairment at early stage and prevents amyloidosis at late stage in APP/PS1 mice

Triggering receptor expressed in myeloid cells (TREM)2 is a genetic high-risk factor for sporadic Alzheimer's disease (AD) and is considered a potential target for AD diagnosis and therapy, although its role in the different stages of AD remains controversial. We generated an embryonic deletion of Trem2 (whole body deletion) and induced hippocampal- and cortical-specific knockdown of microglial Trem2 at different stages of the AD process in amyloid precursor protein/Psen1 mice by adeno-associated virus (AAV) infection. AAV infection induced microglial Trem2 overexpression in the hippocampus of wild-type (WT) and thymus cell antigen 1-enhanced green fluorescent protein mice. Mice were subjected to ethological and pathologic tests. Whole body genetic deletion of Trem2 exerted different electrophysiological outcomes between different AD pathologic stages, which results from a complex integration of synaptic loss and amyloid aggregation. Interestingly, knockdown of Trem2 at the early-middle stage of AD (2-6 mo) prevents synaptic loss through directly inhibiting microglial phagocytosis, whereas knockdown of Trem2 at the middle-late stage of AD (6-10 mo) accelerates synaptic dysfunction because of more severe amyloid deposition caused by the depression of microglial phagocytosis. Additionally, hippocampal overexpression of Trem2 in WT mice results in significant synaptic impairment. Here, with transgenic technology and electrophysiological assay, we revealed that TREM2 up-regulation promotes microglial phagocytosis equally against synapse and amyloid plaques and eventually results in different outcomes. During the early-middle pathologic stage, TREM2 enhancing microglial phagocytosis mainly causes synaptic loss. However, TREM2 up-regulating microglial phagocytosis gradually supports a positive role when amyloid deposition occupies the leading position at the middle-late pathologic stage. In this study, we highlighted that TREM2 triggers synaptic loss during AD pathology development.-Sheng, L., Chen, M., Cai, K., Song, Y., Yu, D., Zhang, H., Xu, G. Microglial Trem2 induces synaptic impairment at early stage and prevents amyloidosis at late stage in APP/PS1 mice.

Investigation of plasma metabolomics and neurotransmitter dysfunction in the process of Alzheimer's disease rat induced by amyloid beta 25-35.

Alzheimer's disease (AD) has become one of the major diseases endangering the health of the elderly. Clarifying the features of each AD animal model is valuable for understanding the onset and progression of diseases and developing potential treatments in the pharmaceutical industry. In this study, we aimed to clarify plasma metabolomics and neurotransmitter dysfunction in the process of AD model rat induced by amyloid beta 25-35 (Aβ 25-35). Firstly, Morris Water Maze (MWM) test was used to investigate cognitive impairment in AD rat after 2, 4 and 8 weeks of modelling. Based on this, the effects on levels of AD-related enzymes and eight neurotransmitters were analyzed. And plasma metabolomics analysis based on ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was used to research the metabolic disturbances in the process of AD rat. The results shown the injury on the spatial learning ability of AD rats was gradually aggravated within 4 weeks, reached the maximum at 4 weeks and then was stable until 8 weeks. During 8 weeks of modeling, the levels of enzymes including β-secretase, γ-secretase, glycogen synthase kinase-3β (GSK-3β), acetyl cholinesterase (AchE) and nitric oxide synthase (NOS) were significant increased in the plasma of AD rats. The neurotransmitter dysfunction was mainly involved in γ-aminobutyric acid (GABA), acetyl choline (Ach), glutamic acid (Glu), 5-hydroxytryptamine (5-HT), dopamine (DA) and norepinephrine (NE). 17 endogenous metabolites correlated with AD were successfully detected in the metabolomics analysis. These metabolites were mainly involved in fatty acids, sphingolipids, and sterols metabolisms, vitamin metabolism, and amino acid metabolism. These metabolites might be the potential biomarkers that correctly mark different stages of AD. The study on peripheral plasma indices reflecting the process of AD laid the foundation for understand the pathophysiology of AD and find an effective and radical cure. And the rules of endogenous metabolic disorder in AD rats also have a certain guiding significance for the future study of food–drug interactions at different stages of AD.

Effective Diagnosis of Alzheimer’s Disease using Modified Decision Tree Classifier

Abstract Alzheimer’s disease (AD) is described as a severe form of the neural disorder that collectively degenerate the essential cognitive activities of a human being (thinking, memory retention, etc.,) in particular among the elderly individuals and eventually results in death. In addition to the adverse ill-health effects on the patients, AD imposes paramount responsibility and burden on the caretakers too. Several genetic and pathological traits and non-invasive diagnostic strategies are being vigorously investigated and explored to discover the early onset of this debilitating disease. The prognosis of AD assumes importance, as the deterioration of health due to its progression may be either contained or controlled. Moreover, early and accurate detection of AD helps medical practitioners to prescribe case-specific medical treatment procedure. Among the popular machine learning algorithms, decision tree technique is widely used for classification/prediction, due to its accuracy and speed.This research article presents a novel decision tree-based classification technique, with optimum hyper parametertuning, that is ideally suitable for AD diagnosis, even at the early stages of development. The performance of this newly proposed Decision Tree Classifier with Hyper Parameters Tuning (DTC-HPT) is validated on the Open Access Imaging Studies Series (OASIS) dataset that contains patients’ data on the different stages of AD. The DTC-HPT is designed with the primary objective to classify the nature of brain abnormality using the most relevantand potentially significant data attributes/parameters. The efficiency of DTC-HPT on AD classification is measured as Accuracy, Precision, Recall, and F1-Score. The correctness of AD classification by DTC-HPTwith an average accuracy of 99.10% endorse that this classification technique can be used for AD detection on the AD clinical datasets.

Analysis of Progression Toward Alzheimer's Disease Based on Evolutionary Weighted Random Support Vector Machine Cluster.

Alzheimer’s disease (AD) could be described into following four stages: healthy control (HC), early mild cognitive impairment (EMCI), late MCI (LMCI) and AD dementia. The discriminations between different stages of AD are considerably important issues for future pre-dementia treatment. However, it is still challenging to identify LMCI from EMCI because of the subtle changes in imaging which are not noticeable. In addition, there were relatively few studies to make inferences about the brain dynamic changes in the cognitive progression from EMCI to LMCI to AD. Inspired by the above problems, we proposed an advanced approach of evolutionary weighted random support vector machine cluster (EWRSVMC). Where the predictions of numerous weighted SVM classifiers are aggregated for improving the generalization performance. We validated our method in multiple binary classifications using Alzheimer’s Disease Neuroimaging Initiative dataset. As a result, the encouraging accuracy of 90% for EMCI/LMCI and 88.89% for LMCI/AD were achieved respectively, demonstrating the excellent discriminating ability. Furthermore, disease-related brain regions underlying the AD progression could be found out on the basis of the amount of discriminative information. The findings of this study provide considerable insight into the neurophysiological mechanisms in AD development.

Exosomes and microRNAs: New potential therapeutic candidates in Alzheimer disease therapy.

Exosomes are biological nanocarriers which could be involved in a variety of basic physiological events. They exert their effects via targeting their cargos (i.e., DNAs, messenger RNAs, microRNAs [miRNAs], and proteins) to host cells, which led to change behaviors of recipient cells. One of the important aspects of exosomes is the roles of them in disease conditions. Increasing evidence indicated that exosomes are one of the main players in Alzheimer's disease (AD) pathogenesis. Hence, it seems that these nanocarriers could be used as diagnostic and therapeutic biomarkers in AD treatment. Another important player in AD pathogenesis is miRNA. MiRNAs are short noncoding RNAs which exert their effects as epigenetic regulators. These molecules involved in different stages of AD. Therefore, miRNAs could be used as prognostic, diagnostic, and therapeutic biomarkers in AD. Here, we summarized various roles of exosomes and application of them in AD pathogenesis. Moreover, we highlighted the utilization of miRNAs as a therapeutic option in AD therapy.

Soluble TREM2 changes during the clinical course of Alzheimer’s disease: A meta-analysis

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a potential and novel biomarker of neuroinflammation implicated in the onset and progression of Alzheimer’s disease (AD). However, previous studies evaluating levels of sTREM2 in different clinical stages of AD have yielded inconsistent results. To clarify the dynamic change of sTREM2 in AD progression, we conducted a meta-analysis of case-control and cohort studies to determine the role of cerebral spinal fluid (CSF) and plasma sTREM2 levels in preclinical AD (pre-AD), mild cognitive impairment (MCI) and AD dementia. We searched PubMed, MEDLINE, EMBASE, the Cochrane Library for English articles and Sinomed, CNKI for Chinese. The associations between sTREM2 levels and AD continuum groups (pre-AD, MCI and AD) were analyzed. We further performed detailed subgroup analysis and meta-regression to detect the sources of heterogeneity. 17 reports comprising 82 patients with pre-AD, 159 with MCI, 598 with AD, as well as 754 controls were included in this analysis. Regarding the sTREM2 levels in CSF, the overall pooled standard mean difference (SMD) revealed significantly elevated sTREM2 levels in the whole AD continuum groups (SMD = 0.48; 95% CI: 0.23, 0.73; P < 0.001) compared with controls. The levels of sTREM2 significantly increased in pre-AD (SMD = 0.47; 95% CI: 0.21, 0.73; P < 0.001), the highest increase occurred in MCI group (SMD = 0.77; 95% CI: -0.05, 1.59; P = 0.066), and the effect size of AD group (SMD = 0.39; 95% CI: 0.13, 0.65; P = 0.004) was also higher compared with control. However, for sTREM2 levels measured in plasma, no significant differences were found (SMD = 0.11; 95% CI: -0.06, 0.27; P = 0.217). Therefore, our study showed that sTREM2 levels increased in the earlier course of AD, and slightly attenuated in dementia stage. The current results indicated that sTREM2 levels fluctuate as a function of clinical stage in AD and it might be a novel inflammatory biomarker involved in different stages of AD.

Age-Related Increase of Insulin-Degrading Enzyme Is Inversely Correlated with Cognitive Function in APPswe/PS1dE9 Mice.

BackgroundInsulin-degrading enzyme (IDE) is an important regulator for Aβ clearance and diabetes. Although it is indispensable in removing plaques related to onset Alzheimer’s disease (AD) and in degrading insulin related to diabetes, there have been few studies on the dynamic level of IDE in different stages of AD.Material/MethodsThe present study explored the level IDE protein in different stages of APPswe/PS1dE9 mice and their correlations with cognitive decline. The 4-month-old, 10-month-old, and 18-month-old mice were used as the different age stages of mice. Cognitive function was evaluated using the Morris water maze test. We also observed the level of Aβ plaques in brain regions of different stages.ResultsThe data revealed that the expression of IDE was dramatically higher than in age-matched wild mice at the age of 10 months and 18 months. In terms of distribution, Aβ plaques were deposited mostly in the cortex and hippocampus, especially in 10-month-old and 18-month-old APPswe/PS1dE9 mice. The cognitive function of 4-month-old APPswe/PS1dE9 mice was not significantly differ in spatial learning. However, the cognitive function, both spatial learning and spatial memory, was dramatically lower in 10-month-old and 18-month-old groups.ConclusionsThere was a positive correlation between the expression of IDE and spatial memory in 10-month-old and 18-month-old APPswe/PS1dE9 mice. The study of this protein may provide reference values for the further study of IDE in Alzheimer’s disease.

Neonatal Neurodegeneration in Alzheimer's Disease Transgenic Mouse Model.

Alzheimer’s disease (AD) is a progressive disorder characterized by a variety of molecular pathologies causing cortical dementia with a prominent memory deficit. Formation of the pathology, which begins decades before the diagnosis of the disease, is highly correlated with the clinical symptoms. Several proteomics studies were performed using animal models to monitor the alterations of the brain tissue proteome at different stages of AD. However, proteome changes in the brain regions of newborn transgenic mouse model have not been investigated yet. To this end, we analyzed protein expression alterations in cortex, hippocampus and cerebellum of transgenic mice carrying five familial AD mutations (5XFAD) at neonatal day-1. Our results indicate a remarkable difference in protein expression profile of newborn 5XFAD brain with region specific variations. Additionally, the proteins, which show similar expression alteration pattern in postmortem human AD brains, were determined. Bioinformatics analysis showed that the molecular alterations were mostly related to the cell morphology, cellular assembly and organization, and neuroinflammation. Moreover, morphological analysis revealed that there is an increase in neurite number of 5XFAD mouse neurons in vitro. We suggest that, molecular alterations in the AD brain exist even at birth, and perhaps the disease is silenced until older ages when the brain becomes vulnerable.