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Motivation. At present, the research methods for image genetics of Alzheimer's disease based on machine learning are mainly divided into three steps: the first step is to preprocess the original image and gene information into digital signals that are easy to calculate; the second step is feature selection aiming at eliminating redundant signals and obtain representative features; and the third step is to build a learning model and predict the unknown data with regression or bivariate correlation analysis. This type of method requires manual extraction of feature single-nucleotide polymorphisms (SNPs), and the extraction process relies on empirical knowledge to a certain extent, such as linkage imbalance and gene function information in a group sparse model, which puts forward certain requirements for applicable scenarios and application personnel. To solve the problems of insufficient biological significance and large errors in the previous methods of association analysis and disease diagnosis, this paper presents a method of correlation analysis and disease diagnosis between SNP and region of interest (ROI) based on a deep learning model. It is a data-driven method, which has no obvious feature selection process. Results. The deep learning method adopted in this paper has no obvious feature extraction process relying on prior knowledge and model assumptions. From the results of correlation analysis between SNP and ROI, this method is complementary to other regression model methods in application scenarios. In order to improve the disease diagnosis performance of deep learning, we use the deep learning model to integrate SNP characteristics and ROI characteristics. The SNP feature, ROI feature, and SNP-ROI joint feature were input into the deep learning model and trained by cross-validation technique. The experimental results show that the SNP-ROI joint feature describes the information of the samples from different angles, which makes the diagnosis accuracy higher. [ABSTRACT FROM AUTHOR]

Mild cognitive impairment (MCI) could be a transitory stage to Alzheimer's disease (AD) and underlines the importance of early detection of this stage. In MCI stage, though the older adults are not completely dependent on others for day-to-day tasks, mild impairments are seen in memory, attention, etc., subtly affecting their daily activities/routines. Smart sensing technologies, such as wearable and non-wearable sensors, coupled with advanced predictive modeling techniques enable daily activities/routines based early detection of MCI symptoms. Non-wearable sensors are less intrusive and can monitor activities at naturalistic environment with no interference to an individual's daily routines. This review seeks to answer the following questions: (1) What is the evidence for use of non-wearable sensor technologies in early detection of MCI/AD utilizing daily activity data in an unobtrusive manner? (2) How are the machine learning methods being employed in analyzing activity data in this early detection approach? A systematic search was conducted in databases such as IEEE Explorer, PubMed, Science Direct, and Google Scholar for the papers published from inception till March 2019. All studies that fulfilled the following criteria were examined: a research goal of detecting/predicting MCI/AD, daily activities data to detect MCI/AD, noninvasive/non-wearable sensors for monitoring activity patterns, and machine learning techniques to create the prediction models. Out of 2165 papers retrieved, 12 papers were eligible for inclusion in this review. This review found a diverse selection of aspects such as sensors, activity domains/features, activity recognition methods, and abnormality detection methods. There is no conclusive evidence on superiority of one or more of these aspects over the others, especially on the activity feature that would be the best indicator of cognitive decline. Though all these studies demonstrate technological developments in this field, they all suggest it is far in the future it becomes an effective diagnostic tool in real-life clinical practice. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most generally known neurodegenerative disorder, leading to a steady deterioration in cognitive ability. Deep learning models have shown outstanding performance in the diagnosis of AD, and these models do not need any handcrafted feature extraction over conventional machine learning algorithms. Since the 2012 AlexNet accomplishment, the convolutional neural network (CNN) has been progressively utilized by the medical community to assist practitioners to early diagnose AD. This paper explores the current cutting edge applications of CNN on single and multimodality (combination of two or more modalities) neuroimaging data for the classification of AD. An exhaustive systematic search is conducted on four notable databases: Google Scholar, IEEE Xplore, ACM Digital Library, and PubMed in June 2021. The objective of this study is to examine the effectiveness of classification approaches on AD to analyze different kinds of datasets, neuroimaging modalities, preprocessing techniques, and data handling methods. However, CNN has achieved great success in the classification of AD; still, there are a lot of challenges particularly due to scarcity of medical imaging data and its possible scope in this field. [ABSTRACT FROM AUTHOR]

Graph Convolutional Networks (GCNs) are widely applied in classification tasks by aggregating the neighborhood information of each sample to output robust node embedding. However, conventional GCN methods do not update the graph during the training process so that their effectiveness is always influenced by the quality of the input graph. Moreover, previous GCN methods lack the interpretability to limit their real applications. In this paper, a novel personalized diagnosis technique is proposed for early Alzheimer's Disease (AD) diagnosis via coupling interpretable feature learning with dynamic graph learning into the GCN architecture. Specifically, the module of interpretable feature learning selects informative features to provide interpretability for disease diagnosis and abandons redundant features to capture inherent correlation of data points. The module of dynamic graph learning adjusts the neighborhood relationship of every data point to output robust node embedding as well as the correlations of all data points to refine the classifier. The GCN module outputs diagnosis results based on the learned inherent graph structure. All three modules are jointly optimized to perform reliable disease diagnosis at an individual level. Experiments demonstrate that our method outputs competitive diagnosis performance as well as provide interpretability for personalized disease diagnosis. • Interpretable learning is used to output interpretable diagnosis results. • Dynamic graph learning coupled with GCN to optimize graph structure. • GCN coupled with above learning are used to output personalized diagnosis. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is an irreversible neurodegenerative disease that results in a progressive decline in cognitive abilities. Since AD starts several years before the onset of the symptoms, its early detection is challenging due to subtle changes in biomarkers mainly detectable in different neuroimaging modalities. Developing computer-aided diagnostic models based on deep learning can provide excellent opportunities for the analysis of different neuroimage modalities along with other non-image biomarkers. In this survey, we perform a comparative analysis of about 100 published papers since 2019 that employ basic deep architectures such as CNN, RNN, and generative models for AD diagnosis. Moreover, about 60 papers that have applied a trending topic or architecture for AD are investigated. Explainable models, normalizing flows, graph-based deep architectures, self-supervised learning, and attention mechanisms are considered. The main challenges in this body of literature have been categorized and explained from data-related, methodology-related, and clinical adoption aspects. We conclude our paper by addressing some future perspectives and providing recommendations to conduct further studies for AD diagnosis. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) affects millions of people and is a major rising problem in health care worldwide. Recent research suggests that AD could have different subtypes, presenting differences in how the disease develops. Characterizing those subtypes could be key to deepen the understanding of this complex disease. In this paper, we used a multivariate, non-supervised clustering method over blood-based markers to find subgroups of patients defined by distinctive blood marker profiles. Our analysis on ADNI database identified 4 possible subgroups, each with a different blood profile. More importantly, we show that subgroups with different profiles have a different relationship between brain phenotypes detected in magnetic resonance imaging and disease condition. [ABSTRACT FROM AUTHOR]

Background: Early diagnosis of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) is essential for timely treatment. Machine learning and multivariate pattern analysis (MVPA) for the diagnosis of brain disorders are explicitly attracting attention in the neuroimaging community. In this paper, we propose a voxel-wise discriminative framework applied to multi-measure resting-state fMRI (rs-fMRI) that integrates hybrid MVPA and extreme learning machine (ELM) for the automated discrimination of AD and MCI from the cognitive normal (CN) state. Materials and methods: We used two rs-fMRI cohorts: the public Alzheimer’s disease Neuroimaging Initiative database (ADNI2) and an in-house Alzheimer’s disease cohort from South Korea, both including individuals with AD, MCI, and normal controls. After extracting three-dimensional (3-D) patterns measuring regional coherence and functional connectivity during the resting state, we performed univariate statistical t-tests to generate a 3-D mask that retained only voxels showing significant changes. Given the initial univariate features, to enhance discriminative patterns, we implemented MVPA feature reduction using support vector machine-recursive feature elimination (SVM-RFE), and least absolute shrinkage and selection operator (LASSO), in combination with the univariate t-test. Classifications were performed by an ELM, and its efficiency was compared to linear and nonlinear (radial basis function) SVMs. Results: The maximal accuracies achieved by the method in the ADNI2 cohort were 98.86% (p<0.001) and 98.57% (p<0.001) for AD and MCI vs. CN, respectively. In the in-house cohort, the same accuracies were 98.70% (p<0.001) and 94.16% (p<0.001). Conclusion: From a clinical perspective, combining extreme learning machine and hybrid MVPA applied on concatenations of multiple rs-fMRI biomarkers can potentially assist the clinicians in AD and MCI diagnosis. [ABSTRACT FROM AUTHOR]

Highlights • We propose a classification method based on multiple cluster dense convolutional neural networks (DenseNets) using MR images for AD diagnosis. • The whole brain image is first partitioned into different local regions. A number of patches are extracted from each region and grouped into different clusters. Multiple cluster DenseNets are built to learn the patch-level features which are further aggregated for region-level representations. The final image classification is made by combining the representations of different regions. The features of MR brain images are gradually learned from the local patches to global image level for the classification task. • The proposed method is a data driven method by jointly learning the features and classification without the domain expert knowledge. There are no rigid registration and segmentation required for preprocessing MR images. • Our experiments on ADNI database have demonstrated the promising classification performances of the proposed algorithm. Abstract Alzheimer's disease (AD) is an irreversible neurodegenerative disorder with progressive impairment of memory and cognitive functions. Structural magnetic resonance images (MRI) play important role to evaluate the brain anatomical changes for AD Diagnosis. Machine learning technologies have been widely studied on MRI computation and analysis for quantitative evaluation and computer-aided-diagnosis of AD. Most existing methods extract the hand-craft features after image processing such as registration and segmentation, and then train a classifier to distinguish AD subjects from other groups. Motivated by the success of deep learning in image classification, this paper proposes a classification method based on multiple cluster dense convolutional neural networks (DenseNets) to learn the various local features of MR brain images, which are combined for AD classification. First, we partition the whole brain image into different local regions and extract a number of 3D patches from each region. Second, the patches from each region are grouped into different clusters with the K-Means clustering method. Third, we construct a DenseNet to learn the patch features for each cluster and the features learned from the discriminative clusters of each region are ensembled for classification. Finally, the classification results from different local regions are combined to enhance final image classification. The proposed method can gradually learn the MRI features from the local patches to global image level for the classification task. There are no rigid registration and segmentation required for preprocessing MRI images. Our method is evaluated using T1-weighted MRIs of 831 subjects including 199 AD patients, 403 mild cognitive impairment (MCI) and 229 normal control (NC) subjects from Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Experimental results show that the proposed method achieves an accuracy of 89.5% and an AUC (area under the ROC curve) of 92.4% for AD vs. NC classification, and an accuracy of 73.8% and an AUC of 77.5% for MCI vs. NC classification, demonstrating the promising classification performances. [ABSTRACT FROM AUTHOR]

In this paper, we developed a new method to detect Alzheimer’s disease (AD)-related amyloid precursor protein (APP). A composite material containing horseradish peroxidase (HRP), APP antibody, and Cu3(PO4)2 was synthesized as the biosensor by co-precipitation method. In this competitive immunoassay, APP was first conjugated onto the microplate surface with the help of poly-L-lysine as the coating reagent; the composite materials were then attached onto the microplate through the interaction of APP and antibody; the HRP can catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) and formed colored species. Therefore, the more APP in the detection solution (free form), the less composite material was combined with the immobilized APP on the microplate, resulting in the production of less colored TMB species. A series of detection parameters were studied, such as the composite material synthesis process, the concentration, and reaction time of different compounds. Our method has higher sensitivity compared with the similar immunoassay without using composite materials (the limits of detection are 0.3 and 3 ng/mL, respectively), and can be used for real samples (human serum) detection. The detection results using our method are consistent with the ELISA results, which is useful for the AD detection.ᅟ [ABSTRACT FROM AUTHOR]

Case-control Genome-Wide Association Studies (GWAS) provide a rich resource for studying the genetic architecture of complex diseases. A key is to elucidate how the genetic effects vary by the environment, what is traditionally defined by Gene-Environment interactions (GxE). The overlooked complication is that multiple, distinct pathophysiologic mechanisms may lead to the same clinical diagnosis and often these mechanisms have distinct genetic bases. In this paper, we first show that using the clinically diagnosed status can lead to severely biased estimates of GxE interactions in situations when the frequency of the pathologic diagnosis of interest, as compared to other diagnoses, depends on the environment. We then propose a pseudo-likelihood solution to correct the bias. Finally, we demonstrate our method in extensive simulations and in a GWAS of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Although the hippocampus is one of the most studied structures in the human brain, limited quantitative data exist on its 3D organization, anatomical variability, and effects of disease on its subregions. Histological studies provide restricted reference information due to their 2D nature. In this paper, high-resolution (~200 x 200 x 200 µm³) ex vivo MRI scans of 31 human hippocampal specimens are combined using a groupwise diffeomorphic registration approach into a 3D probabilistic atlas that captures average anatomy and anatomic variability of hippocampal subfields. Serial histological imaging in 9 of the 31 specimens was used to label hippocampal subfields in the atlas based on cytoarchitecture. Specimens were obtained from autopsies in patients with a clinical diagnosis of Alzheimer's disease (AD; 9 subjects, 13 hemispheres), of other dementia (nine subjects, nine hemispheres), and in subjects without dementia (seven subjects, nine hemispheres), and morphometric analysis was performed in atlas space to measure effects of age and AD on hippocampal subfields. Disproportional involvement of the cornu ammonis (CA) 1 subfield and stratum radiatum lacunosum moleculare was found in AD, with lesser involvement of the dentate gyrus and CA2/3 subfields. An association with age was found for the dentate gyrus and, to a lesser extent, for CA1. Three-dimensional patterns of variability and disease and aging effects discovered via the ex vivo hippocampus atlas provide information highly relevant to the active field of in vivo hippocampal subfield imaging. [ABSTRACT FROM AUTHOR]

Early diagnosis is critical for individuals with Alzheimer's disease (AD) in clinical practice because its progress is irreversible. In the existing literature, support vector machine (SVM) has always been applied to distinguish between AD and healthy controls (HC) based on neuroimaging data. But previous studies have only used a single SVM to classify AD and HC, and the accuracy is not very high and generally less than 90%. The method of random support vector machine cluster was proposed to classify AD and HC in this paper. From the Alzheimer's Disease Neuroimaging Initiative database, the subjects including 25 AD individuals and 35 HC individuals were obtained. The classification accuracy could reach to 94.44% in the results. Furthermore, the method could also be used for feature selection and the accuracy could be maintained at the level of 94.44%. In addition, we could also find out abnormal brain regions (inferior frontal gyrus, superior frontal gyrus, precentral gyrus and cingulate cortex). It is worth noting that the proposed random support vector machine cluster could be a new insight to help the diagnosis of AD. [ABSTRACT FROM AUTHOR]

Neuroscience is of emerging importance along with the contributions of Operational Research to the practices of diagnosing neurodegenerative diseases with computer-aided systems based on brain image analysis. Although multiple biomarkers derived from Magnetic Resonance Imaging (MRI) data have proven to be effective in diagnosing Alzheimer's disease (AD) and mild cognitive impairment (MCI), no specific system has yet been a part of routine clinical practice. This paper aims to introduce a fully-automated voxel-based procedure, Voxel-MARS, for detection of AD and MCI in early stages of progression. Performance was evaluated on a dataset of 508 MRI volumes gathered from the Alzheimer's Disease Neuroimaging Initiative database. Data were transformed into a high-dimensional space through a feature extraction process. A novel 3-step feature selection procedure was applied. Multivariate Adaptive Regression Splines method was used as a classifier for the first time in the field of brain MRI analysis. The results were compared to those presented in a previous study on 28 voxel-based methods in terms of their ability to separate control normal (CN) subjects from the ones diagnosed with AD and MCI. It was observed that our method outperformed all of the others in sensitivity (83.58% in AD/CN and 78.38% in MCI/CN classification) with acceptable specificity values (over 85% in both cases). Furthermore, the method worked for discriminating MCI patients which converted to AD in 18 months (MCIc) from non-converters (MCInc) with a sensitivity outcome better than 27 of 28 methods. Overall, it was shown that the proposed method is promising in early detection of AD. [ABSTRACT FROM AUTHOR]

Background: Increasing age is the biggest risk factor for dementia, of which Alzheimer's disease is the commonest cause. The pathological changes underpinning Alzheimer's disease are thought to develop at least a decade prior to the onset of symptoms. Molecular positron emission tomography and multi-modal magnetic resonance imaging allow key pathological processes underpinning cognitive impairment - including β-amyloid depostion, vascular disease, network breakdown and atrophy - to be assessed repeatedly and non-invasively. This enables potential determinants of dementia to be delineated earlier, and therefore opens a pre-symptomatic window where intervention may prevent the onset of cognitive symptoms.Methods/design: This paper outlines the clinical, cognitive and imaging protocol of "Insight 46", a neuroscience sub-study of the MRC National Survey of Health and Development. This is one of the oldest British birth cohort studies and has followed 5362 individuals since their birth in England, Scotland and Wales during one week in March 1946. These individuals have been tracked in 24 waves of data collection incorporating a wide range of health and functional measures, including repeat measures of cognitive function. Now aged 71 years, a small fraction have overt dementia, but estimates suggest that ~1/3 of individuals in this age group may be in the preclinical stages of Alzheimer's disease. Insight 46 is recruiting 500 study members selected at random from those who attended a clinical visit at 60-64 years and on whom relevant lifecourse data are available. We describe the sub-study design and protocol which involves a prospective two time-point (0, 24 month) data collection covering clinical, neuropsychological, β-amyloid positron emission tomography and magnetic resonance imaging, biomarker and genetic information. Data collection started in 2015 (age 69) and aims to be completed in 2019 (age 73).Discussion: Through the integration of data on the socioeconomic environment and on physical, psychological and cognitive function from 0 to 69 years, coupled with genetics, structural and molecular imaging, and intensive cognitive and neurological phenotyping, Insight 46 aims to identify lifetime factors which influence brain health and cognitive ageing, with particular focus on Alzheimer's disease and cerebrovascular disease. This will provide an evidence base for the rational design of disease-modifying trials. [ABSTRACT FROM AUTHOR]

The global impact of Alzheimer's disease (AD) continues to increase, and focused efforts are needed to address this immense public health challenge. National leaders have set a goal to prevent or effectively treat AD by 2025. In this paper, we discuss the path to 2025, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs). Under the current conditions, only drugs currently in late Phase 1 or later will have a chance of being approved by 2025. If pipeline attrition rates remain high, only a few compounds at best will meet this time frame. There is an opportunity to reduce the time and risk of AD drug development through an improvement in trial design; better trial infrastructure; disease registries of well-characterized participant cohorts to help with more rapid enrollment of appropriate study populations; validated biomarkers to better detect disease, determine risk and monitor disease progression as well as predict disease response; more sensitive clinical assessment tools; and faster regulatory review. To implement change requires efforts to build awareness, educate and foster engagement; increase funding for both basic and clinical research; reduce fragmented environments and systems; increase learning from successes and failures; promote data standardization and increase wider data sharing; understand AD at the basic biology level; and rapidly translate new knowledge into clinical development. Improved mechanistic understanding of disease onset and progression is central to more efficient AD drug development and will lead to improved therapeutic approaches and targets. The opportunity for more than a few new therapies by 2025 is small. Accelerating research and clinical development efforts and bringing DMTs to market sooner would have a significant impact on the future societal burden of AD. As these steps are put in place and plans come to fruition, e.g., approval of a DMT, it can be predicted that momentum will build, the process will be self-sustaining, and the path to 2025, and beyond, becomes clearer. [ABSTRACT FROM AUTHOR]

The quantification of neurofibrillary tangles (NFTs) using specific PET tracers can facilitate the diagnosis of Alzheimer's disease (AD) and allow monitoring of disease progression and treatment efficacy. [18F]-THK523 has shown high affinity and selectivity for tau pathology. However, its high retention in white matter, which makes simple visual inspection difficult, may limit its use in research or clinical settings. In this paper, we optimized the automated radiosynthesis of [11C]-TKF and evaluated its biodistribution and toxicity in C57 mice. [11C]-TKF can be made by reaction precursor with [11C]MeOTf or 11CH3I, but [11C]MeOTf will give us higher labeling yields and specific activity. [11C]-TKF presented better brain uptake in normal mouse than [18F]-THK523 (3.23% ± 1.25% ID.g-1 vs. 2.62% ± 0.39% ID.g-1 at 2 min post-injection). The acute toxicity studies of [11C]-TKF were unremarkable. [ABSTRACT FROM AUTHOR]

Multitemplate-based brain morphometric pattern analysis using magnetic resonance imaging has been recently proposed for automatic diagnosis of Alzheimer's disease (AD) and its prodromal stage (i.e., mild cognitive impairment or MCI). In such methods, multiview morphological patterns generated from multiple templates are used as feature representation for brain images. However, existing multitemplate-based methods often simply assume that each class is represented by a specific type of data distribution (i.e., a single cluster), while in reality, the underlying data distribution is actually not preknown. In this paper, we propose an inherent structure-based multiview leaning method using multiple templates for AD/MCI classification. Specifically, we first extract multiview feature representations for subjects using multiple selected templates and then cluster subjects within a specific class into several subclasses (i.e., clusters) in each view space. Then, we encode those subclasses with unique codes by considering both their original class information and their own distribution information, followed by a multitask feature selection model. Finally, we learn an ensemble of view-specific support vector machine classifiers based on their, respectively, selected features in each view and fuse their results to draw the final decision. Experimental results on the Alzheimer's Disease Neuroimaging Initiative database demonstrate that our method achieves promising results for AD/MCI classification, compared to the state-of-the-art multitemplate-based methods. [ABSTRACT FROM AUTHOR]

The high feature-dimension and low sample-size problem is one of the major challenges in the study of computer-aided Alzheimer's disease (AD) diagnosis. To circumvent this problem, feature selection and subspace learning have been playing core roles in the literature. Generally, feature selection methods are preferable in clinical applications due to their ease for interpretation, but subspace learning methods can usually achieve more promising results. In this paper, we combine two different methodological approaches to discriminative feature selection in a unified framework. Specifically, we utilize two subspace learning methods, namely, linear discriminant analysis and locality preserving projection, which have proven their effectiveness in a variety of fields, to select class-discriminative and noise-resistant features. Unlike previous methods in neuroimaging studies that mostly focused on a binary classification, the proposed feature selection method is further applicable for multiclass classification in AD diagnosis. Extensive experiments on the Alzheimer's disease neuroimaging initiative dataset showed the effectiveness of the proposed method over other state-of-the-art methods. [ABSTRACT FROM PUBLISHER]

Complex biological systems are organized across various spatiotemporal scales with particular scientific disciplines dedicated to the study of each scale (e.g. genetics, molecular biology and cognitive neuroscience). When considering disease pathophysiology, one must contemplate the scale at which the disease process is being observed and how these processes impact other levels of organization. Historically Alzheimer's disease has been viewed as a disease of abnormally aggregated proteins by pathologists and molecular biologists and a disease of clinical symptoms by neurologists and psychologists. Bridging the divide between these scales has been elusive, but the study of brain networks appears to be a pivotal inroad to accomplish this task. In this study, we were guided by an emerging systems-based conceptualization of Alzheimer's disease and investigated changes in brain networks across the disease spectrum. The default mode network has distinct subsystems with unique functional-anatomic connectivity, cognitive associations, and responses to Alzheimer's pathophysiology. These distinctions provide a window into the systems-level pathophysiology of Alzheimer's disease. Using clinical phenotyping, metadata, and multimodal neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative, we characterized the pattern of default mode network subsystem connectivity changes across the entire disease spectrum (n = 128). The two main findings of this paper are (i) the posterior default mode network fails before measurable amyloid plaques and appears to initiate a connectivity cascade that continues throughout the disease spectrum; and (ii) high connectivity between the posterior default mode network and hubs of high connectivity (many located in the frontal lobe) is associated with amyloid accumulation. These findings support a system model best characterized by a cascading network failure--analogous to cascading failures seen in power grids triggered by local overloads proliferating to downstream nodes eventually leading to widespread power outages, or systems failures. The failure begins in the posterior default mode network, which then shifts processing burden to other systems containing prominent connectivity hubs. This model predicts a connectivity 'overload' that precedes structural and functional declines and recasts the interpretation of high connectivity from that of a positive compensatory phenomenon to that of a load-shifting process transiently serving a compensatory role. It is unknown whether this systems-level pathophysiology is the inciting event driving downstream molecular events related to synaptic activity embedded in these systems. Possible interpretations include that the molecular-level events drive the network failure, a pathological interaction between the network-level and the molecular-level, or other upstream factors are driving both. [ABSTRACT FROM AUTHOR]

Recently, several pattern recognition methods have been proposed to automatically discriminate between patients with and without Alzheimer's disease using different imaging modalities: sMRI, fMRI, PET and SPECT. Classical approaches in visual information retrieval have been successfully used for analysis of structural MRI brain images. In this paper, we use the visual indexing framework and pattern recognition analysis based on structural MRI data to discriminate three classes of subjects: normal controls (NC), mild cognitive impairment (MCI) and Alzheimer's disease (AD). The approach uses the circular harmonic functions (CHFs) to extract local features from the most involved areas in the disease: hippocampus and posterior cingulate cortex (PCC) in each slice in all three brain projections. The features are quantized using the Bag-of-Visual-Words approach to build one signature by brain (subject). This yields a transformation of a full 3D image of brain ROIs into a 1D signature, a histogram of quantized features. To reduce the dimensionality of the signature, we use the PCA technique. Support vector machines classifiers are then applied to classify groups. The experiments were conducted on a subset of ADNI dataset and applied to the “Bordeaux-3City” dataset. The results showed that our approach achieves respectively for ADNI dataset and “Bordeaux-3City” dataset; for AD vs NC classification, an accuracy of 83.77% and 78%, a specificity of 88.2% and 80.4% and a sensitivity of 79.09% and 74.7%. For NC vs MCI classification we achieved for the ADNI datasets an accuracy of 69.45%, a specificity of 74.8% and a sensitivity of 62.52%. For the most challenging classification task (AD vs MCI), we reached an accuracy of 62.07%, a specificity of 75.15% and a sensitivity of 49.02%. The use of PCC visual features description improves classification results by more than 5% compared to the use of hippocampus features only. Our approach is automatic, less time-consuming and does not require the intervention of the clinician during the disease diagnosis. [ABSTRACT FROM AUTHOR]

Objective This paper proposes a new, complex algorithm for the blind classification of the original electroencephalogram (EEG) tracing of each subject, without any preliminary pre-processing. The medical need in this field is to reach an early differential diagnosis between subjects affected by mild cognitive impairment (MCI), early Alzheimer's disease (AD) and the healthy elderly (CTR) using only the recording and the analysis of few minutes of their EEG. Methods and material This study analyzed the EEGs of 272 subjects, recorded at Rome's Neurology Unit of the Policlinico Campus Bio-Medico. The EEG recordings were performed using 19 electrodes, in a 0.3–70 Hz bandpass, positioned according to the International 10–20 System. Many powerful learning machines and algorithms have been proposed during the last 20 years to effectively resolve this complex problem, resulting in different and interesting outcomes. Among these algorithms, a new artificial adaptive system, named implicit function as squashing time (I-FAST), is able to diagnose, with high accuracy, a few minutes of the subject's EEG track; whether it manifests an AD, MCI or CTR condition. An updating of this system, carried out by adding a new algorithm, named multi scale ranked organizing maps (MS-ROM), to the I-FAST system, is presented, in order to classify with greater accuracy the unprocessed EEG's of AD, MCI and control subjects. Results The proposed system has been measured on three independent pattern recognition tasks from unprocessed EEG tracks of a sample of AD subjects, MCI subjects and CTR: (a) AD compared with CTR; (b) AD compared with MCI; (c) CTR compared with MCI. While the values of accuracy of the previous system in distinguishing between AD and MCI were around 92%, the new proposed system reaches values between 94% and 98%. Similarly, the overall accuracy with best artificial neural networks (ANNs) is 98.25% for the distinguishing between CTR and MCI. Conclusions This new version of I-FAST makes different steps forward: (a) avoidance of pre-processing phase and filtering procedure of EEG data, being the algorithm able to directly process an unprocessed EEG; (b) noise elimination, through the use of a training variant with input selection and testing system, based on naïve Bayes classifier; (c) a more robust classification phase, showing the stability of results on nine well known learning machine algorithms; (d) extraction of spatial invariants of an EEG signal using, in addition to the unsupervised ANN, the principal component analysis and the multi scale entropy, together with the MS-ROM; a more accurate performance in this specific task. [ABSTRACT FROM AUTHOR]

Overexpression of the amyloid precursor protein (APP) and the hyperphosphorylation of the tau protein are vital in the understanding of the cause of Alzheimer's disease (AD). As a consequence, regulation of the expression of both APP and tau proteins is one important approach in combating AD. The APP and tau proteins can be targeted at the levels of transcription, translation and protein structural integrity. This paper reports the utilization of a bi-cistronic vector containing either APP or tau internal ribosome entry site (IRES) elements flanked by ß-galactosidase gene (cap-dependent) and secreted alkaline phosphatase (SEAP) (cap-independent) to discern the mechanism of action of memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist. Results indicate that memantine could reduce the activity of both the APP and tau IRES at a concentration of ~10 µM (monitored by SEAP activity) without interfering with the cap-dependent translation as monitored by the ß-galactosidase assay. Western blot analysis of the tau protein in neuroblastoma (N2A) and rat hippocampal cells confirmed the halting of the expression of the tau proteins. We also employed this approach to identify a preparation named NB34, extracts of Boussingaultia baselloides (madeira-vine) fermented with Lactobacillus spp., which can function similarly to memantine in both IRES of APP and Tau. The water maze test demonstrated that NB34 could improve the spatial memory of a high fat diet induced neurodegeneration in apolipoprotein E-knockout (ApoE-/-) mice. These results revealed that the bi-cistronic vector provided a simple, and effective platform in screening and establishing the mechanistic action of potential compounds for the treatment and management of AD. [ABSTRACT FROM AUTHOR]

This paper proposes to combine MRI data with a neuropsychological test, mini-mental state examination (MMSE), as input to a multi-dimensional space for the classification of Alzheimer's disease (AD) and it's prodromal stages—mild cognitive impairment (MCI) including amnestic MCI (aMCI) and nonamnestic MCI (naMCI). The decisional space is constructed using those features deemed statistically significant through an elaborate feature selection and ranking mechanism. FreeSurfer was used to calculate 55 volumetric variables, which were then adjusted for intracranial volume, age and education. The classification results obtained using support vector machines are based on twofold cross validation of 50 independent and randomized runs. The study included 59 AD, 67 aMCI, 56 naMCI, and 127 cognitively normal (CN) subjects. The study shows that MMSE scores contain the most discriminative power of AD, aMCI, and naMCI. For AD versus CN, the two most discriminative volumetric variables (right hippocampus and left inferior lateral ventricle), when combined with MMSE scores, provided an average accuracy of 92.4% (sensitivity: 84.0%; specificity: 96.1%). MMSE scores are found to improve all classifications with accuracy increments of 8.2% and 12% for aMCI versus CN and naMCI versus CN, respectively. Results also show that brain atrophy is almost evenly seen on both sides of the brain for AD subjects, which is different from right-side dominance for aMCI and left-side dominance for naMCI. Furthermore, hippocampal atrophy is seen to be the most significant for aMCI, while Accumbens area and ventricle are most significant for naMCI. [ABSTRACT FROM PUBLISHER]

Objectives: The objective of this systematic review was (1) to give an overview of the available short screening instruments for the early detection of Alzheimer's disease (AD) and (2) to review the psychometric properties of these instruments. Methods: First, a systematic search of titles and abstracts of PubMed and Web of Science was conducted between February and July 2015 and updated in April 2016 and May 2018. Only papers written in English or Dutch were considered. All full-text papers about cognitive screening instruments for the early detection of AD were included, resulting in the identification of 38 pencil and paper tests and 12 computer tests. In a second step, the psychometric quality of these instruments was evaluated. Therefore, the same databases were searched again to identify papers that described the psychometric properties of the instruments meanwhile applying diagnostic criteria for the diagnostic groups included. Results: Out of 1454 papers, 96 clearly discussed the psychometric properties of the instruments. Eighty-nine papers discussed pencil and paper tests of which 80 were validated in a memory clinic setting. Based on the number of studies (31 articles) and the sensitivity (84%) and specificity (74%) values, the Montreal Cognitive Assessment (MoCA) seems to be a promising (pencil and paper) screening test for memory clinic testing as well as for population screening. Regarding computer tests, validation studies were only available for 7 out of 12 tests. Conclusions: A large number of screening tests for AD are available. However, most tests are only validated in a memory clinic setting and description of the psychometric properties of the instruments is limited. Especially, computer tests require further research. The MoCA is a promising instrument, but the specificity to detect early AD is rather low. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) represents the prevalent type of dementia in the elderly, and is characterized by the presence of neurofibrillary tangles and amyloid plaques that eventually leads to the loss of neurons, resulting in atrophy in specific brain areas. Although the process of degeneration can be visualized through various modalities of medical imaging and has proved to be a valuable biomarker, the accurate diagnosis of Alzheimer’s disease remains a challenge, especially in its early stages. In this paper, we propose a novel classification method for Alzheimer’s disease/cognitive normal discrimination in structural magnetic resonance images (MRI), based on the extension of the concept of histons to volumetric images. The proposed method exploits the relationship between grey matter, white matter and cerebrospinal fluid degeneration by means of a segmentation using supervoxels. The calculated histons are then processed for a reduction in dimensionality using principal components analysis (PCA) and the resulting vector is used to train an support vector machine (SVM) classifier. Experimental results using the OASIS-1 database have proven to be a significant improvement compared to a baseline classification made using the pipeline provided by Clinica software. [ABSTRACT FROM AUTHOR]