Search Results (64)

In this study, we address the early detection challenges of Alzheimer’s disease (AD) using explainable artificial intelligence (XAI) techniques. AD, characterized by amyloid plaques and tau tangles, leads to cognitive decline and remains hard to diagnose due to genetic and environmental factors. Utilizing deep learning models, we analyzed brain MRI scans from the ADNI database, categorizing them into normal cognition (NC), mild cognitive impairment (MCI), and AD. The ResNet-50 architecture was employed, enhanced by a channel-wise attention mechanism to improve feature extraction. To ensure model transparency, we integrated local interpretable model-agnostic explanations (LIMEs) and gradient-weighted class activation mapping (Grad-CAM), highlighting significant image regions contributing to predictions. Our model achieved 85% accuracy, effectively distinguishing between the classes. The LIME and Grad-CAM visualizations provided insights into the model’s decision-making process, particularly emphasizing changes near the hippocampus for MCI. These XAI methods enhance the interpretability of AI-driven AD diagnosis, fostering trust and aiding clinical decision-making. Our approach demonstrates the potential of combining deep learning with XAI for reliable and transparent medical applications. Full article

Takayasu’s arteritis (TAK) manifests as an insidiously progressive and debilitating form of granulomatous inflammation including the aorta and its major branches. The precise etiology of TAK remains elusive, with current understanding suggesting an autoimmune origin primarily driven by T cells. Notably, a growing body of evidence bears testimony to the widespread effects of B cells on disease pathogenesis and progression. Distinct alterations in peripheral B cell subsets have been described in individuals with TAK. Advancements in technology have facilitated the identification of novel autoantibodies in TAK. Moreover, emerging data suggest that dysregulated signaling cascades downstream of B cell receptor families, including interactions with innate pattern recognition receptors such as toll-like receptors, as well as co-stimulatory molecules like CD40, CD80 and CD86, may result in the selection and proliferation of autoreactive B cell clones in TAK. Additionally, ectopic lymphoid neogenesis within the aortic wall of TAK patients exhibits functional characteristics. In recent decades, therapeutic interventions targeting B cells, notably utilizing the anti-CD20 monoclonal antibody rituximab, have demonstrated efficacy in TAK. Despite the importance of the humoral immune response, a systematic understanding of how autoreactive B cells contribute to the pathogenic process is still lacking. This review provides a comprehensive overview of the biological significance of B cell-mediated autoimmunity in TAK pathogenesis, as well as insights into therapeutic strategies targeting the humoral response. Furthermore, it examines the roles of T-helper and T follicular helper cells in humoral immunity and their potential contributions to disease mechanisms. We believe that further identification of the pathogenic role of autoimmune B cells and the underlying regulation system will lead to deeper personalized management of TAK patients. We believe that further elucidation of the pathogenic role of autoimmune B cells and the underlying regulatory mechanisms holds promise for the development of personalized approaches to managing TAK patients. Full article

Modularity and resilience are fundamental properties of brain network organization and function. The interplay of these network characteristics is integral to understanding brain vulnerability, network efficiency, and neurocognitive disorders. One potential methodology to explore brain network modularity and resilience is through percolation theory, a sub-branch of graph theory that simulates lesions across brain networks. In this work, percolation theory is applied to connectivity matrices derived from functional MRI from human, mice, and null networks. Nodes, or regions, with the highest betweenness centrality, a graph theory quantifier that examines shortest paths, were sequentially removed from the network. This attack methodology led to a rapid fracturing of the network, resulting in two terminal modules connected by one transfer module. Additionally, preceding the rapid network fracturing, the average betweenness centrality of the network peaked in value, indicating a critical point in brain network functionality. Thus, this work introduces a methodological perspective to identify hubs within the brain based on critical points that can be used as an architectural framework for a neural network. By applying percolation theory to functional brain networks through a network phase-transition lens, network sub-modules are identified using local spikes in betweenness centrality as an indicator of brain criticality. This modularity phase transition provides supporting evidence of the brain functioning at a near-critical point while showcasing a formalism to understand the computational efficiency of the brain as a neural network. Full article

Mild Cognitive Impairment (MCI) is a cognitive state frequently observed in older adults, characterized by significant alterations in memory, thinking, and reasoning abilities that extend beyond typical cognitive decline. It is worth noting that around 10–15% of individuals with MCI are projected to develop Alzheimer’s disease, effectively positioning MCI as an early stage of Alzheimer’s. In this study, a novel approach is presented involving the utilization of eXtreme Gradient Boosting to predict the onset of Alzheimer’s disease during the MCI stage. The methodology entails utilizing data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Through the analysis of longitudinal data, spanning from the baseline visit to the 12-month follow-up, a predictive model was constructed. The proposed model calculates, over a 36-month period, the likelihood of progression from MCI to Alzheimer’s disease, achieving an accuracy rate of 85%. To further enhance the precision of the model, this study implements feature selection using the Recursive Feature Elimination technique. Additionally, the Shapley method is employed to provide insights into the model’s decision-making process, thereby augmenting the transparency and interpretability of the predictions. Full article

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, yet its current treatments are limited to stopping disease progression. Moreover, the effectiveness of these treatments remains uncertain due to the heterogeneity of the disease. Therefore, it is essential to identify disease subtypes at a very early stage. Current data-driven approaches can be used to classify subtypes during later stages of AD or related disorders, but making predictions in the asymptomatic or prodromal stage is challenging. Furthermore, the classifications of most existing models lack explainability, and these models rely solely on a single modality for assessment, limiting the scope of their analysis. Thus, we propose a multimodal framework that utilizes early-stage indicators, including imaging, genetics, and clinical assessments, to classify AD patients into progression-specific subtypes at an early stage. In our framework, we introduce a tri-modal co-attention mechanism (Tri-COAT) to explicitly capture cross-modal feature associations. Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (slow progressing = 177, intermediate = 302, and fast = 15) were used to train and evaluate Tri-COAT using a 10-fold stratified cross-testing approach. Our proposed model outperforms baseline models and sheds light on essential associations across multimodal features supported by known biological mechanisms. The multimodal design behind Tri-COAT allows it to achieve the highest classification area under the receiver operating characteristic curve while simultaneously providing interpretability to the model predictions through the co-attention mechanism. Full article

When integrating data from multiple sources, a common challenge is block-wise missing. Most existing methods address this issue only in cross-sectional studies. In this paper, we propose a method for variable selection when combining datasets from multiple sources in longitudinal studies. To account for block-wise missing in covariates, we impute the missing values multiple times based on combinations of samples from different missing pattern and predictors from different data sources. We then use these imputed data to construct estimating equations, and aggregate the information across subjects and sources with the generalized method of moments. We employ the smoothly clipped absolute deviation penalty in variable selection and use the extended Bayesian Information Criterion criteria for tuning parameter selection. We establish the asymptotic properties of the proposed estimator, and demonstrate the superior performance of the proposed method through numerical experiments. Furthermore, we apply the proposed method in the Alzheimer’s Disease Neuroimaging Initiative study to identify sensitive early-stage biomarkers of Alzheimer’s Disease, which is crucial for early disease detection and personalized treatment. Full article

This study investigates the sex-specific role of the Hypothalamic–Pituitary–Gonadal axis in Alzheimer’s disease progression, utilizing ADNI1 data for 493 individuals, analyzing plasma levels of gonadotropic and sex hormones, and examining neurodegeneration-related brain structures. We assessed plasma levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P4), and testosterone (T), along with volumetric measures of the hippocampus, entorhinal cortex, and hypothalamic subunits, to explore their correlation with Alzheimer’s disease markers across different cognitive statuses and sexes. Significant cognitive status effects were observed for all volumetric measures, with a distinct sex-by-cognitive status interaction for hypothalamic volume, indicating a decrease in males but not in females across cognitive impairment stages. Regression analyses showed specific hypothalamic subunit volume related to hormone levels, accounting for up to approximately 40% of the variance (p < 0.05). The findings highlight sex differences in neurodegeneration and hormonal regulation, suggesting potential for personalized treatments and advancing the understanding of Alzheimer’s disease etiology. Full article

Alzheimer’s disease (AD) exhibits sex-linked variations, with women having a higher prevalence, and little is known about the sexual dimorphism in progressing from Mild Cognitive Impairment (MCI) to AD. The main aim of our study was to shed light on the sex-specific conversion-to-AD risk factors using Random Survival Forests (RSF), a Machine Learning survival approach, and Shapley Additive Explanations (SHAP) on dementia biomarkers in stable (sMCI) and progressive (pMCI) patients. With this purpose, we built two separate models for male (M-RSF) and female (F-RSF) cohorts to assess whether global explanations differ between the sexes. Similarly, SHAP local explanations were obtained to investigate changes across sexes in feature contributions to individual risk predictions. The M-RSF achieved higher performance on the test set (0.87) than the F-RSF (0.79), and global explanations of male and female models had limited similarity (<71.1%). Common influential variables across the sexes included brain glucose metabolism and CSF biomarkers. Conversely, the M-RSF had a notable contribution from hippocampus, which had a lower impact on the F-RSF, while verbal memory and executive function were key contributors only in F-RSF. Our findings confirmed that females had a higher risk of progressing to dementia; moreover, we highlighted distinct sex-driven patterns of variable importance, uncovering different feature contribution risks across sexes that decrease/increase the conversion-to-AD risk. Full article

Patients with Alzheimer’s disease (AD) often present with imaging features indicative of small-vessel injury, among which, white-matter hyperintensities (WMHs) are the most prevalent. However, the underlying mechanism of the association between AD and small-vessel injury is still obscure. The aim of this study is to investigate the mechanism of small-vessel injury in AD. Differential gene expression analyses were conducted to identify the genes related to WMHs separately in mild cognitive impairment (MCI) and cognitively normal (CN) subjects from the ADNI database. The WMH-related genes identified in patients with MCI were considered to be associated with small-vessel injury in early AD. Functional enrichment analyses and a protein–protein interaction (PPI) network were performed to explore the pathway and hub genes related to the mechanism of small-vessel injury in MCI. Subsequently, the Boruta algorithm and support vector machine recursive feature elimination (SVM-RFE) algorithm were performed to identify feature-selection genes. Finally, the mechanism of small-vessel injury was analyzed in MCI from the immunological perspectives; the relationship of feature-selection genes with various immune cells and neuroimaging indices were also explored. Furthermore, 5×FAD mice were used to demonstrate the genes related to small-vessel injury. The results of the logistic regression analyses suggested that WMHs significantly contributed to MCI, the early stage of AD. A total of 276 genes were determined as WMH-related genes in patients with MCI, while 203 WMH-related genes were obtained in CN patients. Among them, only 15 genes overlapped and were thus identified as the crosstalk genes. By employing the Boruta and SVM-RFE algorithms, CD163, ALDH3B1, MIR22HG, DTX2, FOLR2, ALDH2, and ZNF23 were recognized as the feature-selection genes linked to small-vessel injury in MCI. After considering the results from the PPI network, CD163 was finally determined as the critical WMH-related gene in MCI. The expression of CD163 was correlated with fractional anisotropy (FA) values in regions that are vulnerable to small-vessel injury in AD. The immunostaining and RT-qPCR results from the verifying experiments demonstrated that the indicators of small-vessel injury presented in the cortical tissue of 5×FAD mice and related to the upregulation of CD163 expression. CD163 may be the most pivotal candidates related to small-vessel injury in early AD. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder that leads to the loss of cognitive functions due to the deterioration of brain tissue. Current diagnostic methods are often invasive or costly, limiting their widespread use. Developing non-invasive and cost-effective screening methods is crucial, especially for identifying patients with mild cognitive impairment (MCI) at the risk of developing Alzheimer’s disease. This study employs a Machine Learning (ML) approach, specifically K-means clustering, on a subset of pixels common to all magnetic resonance imaging (MRI) images to rapidly classify subjects with AD and those with normal Normal Cognitive (NC). In particular, we benefited from defining significant pixels, a narrow subset of points (in the range of 1.5% to 6% of the total) common to all MRI images and related to more intense degeneration of white or gray matter. We performed K-means clustering, with k = 2, on the significant pixels of AD and NC MRI images to separate subjects belonging to the two classes and detect the class centroids. Subsequently, we classified subjects with MCI using only the significant pixels. This approach enables quick classification of subjects with AD and NC, and more importantly, it predicts MCI-to-AD conversion with high accuracy and low computational cost, making it a rapid and effective diagnostic tool for real-time assessments. Full article

Cortical uptake in brain amyloid positron emission tomography (PET) is increasingly used for the biological diagnosis of Alzheimer’s disease (AD); however, the clinical and biological relevance of the striatum beyond the cortex in amyloid PET scans remains unclear. A total of 513 amyloid-positive participants having 18F-AV45 amyloid PET scans available were included in the analysis. The associations between cognitive scores and striatal uptake were analyzed. The participants were categorized into three groups based on the residual from the linear fitting between 18F-AV45 uptake in the putamen and the cortex in the order of HighP > MidP > LowP group. We then examined the differences between these three groups in terms of clinical diagnosis, APOE genotype, CSF phosphorylated tau (ptau) concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate to evaluate the additional insights provided by the putamen beyond the cortex. The 18F-AV45 uptake in the putamen was more strongly associated with ADAS-cog13 and MoCA scores (p < 0.001) compared to the uptake in the caudate nucleus. Despite comparable cortical uptakes, the HighP group had a two-fold higher risk of being ε4-homozygous or diagnosed with AD dementia compared to the LowP group. These three groups had significantly different CSF ptau concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate. These findings suggest that the assessment of 18F-AV45 uptake in the putamen is of unique value for evaluating disease severity and predicting disease progression. Full article

Background: Predicting cognition decline in patients with mild cognitive impairment (MCI) is crucial for identifying high-risk individuals and implementing effective management. To improve predicting MCI-to-AD conversion, it is necessary to consider various factors using explainable machine learning (XAI) models which provide interpretability while maintaining predictive accuracy. This study used the Explainable Boosting Machine (EBM) model with multimodal features to predict the conversion of MCI to AD during different follow-up periods while providing interpretability. Methods: This retrospective case-control study is conducted with data obtained from the ADNI database, with records of 1042 MCI patients from 2006 to 2022 included. The exposures included in this study were MRI biomarkers, cognitive scores, demographics, and clinical features. The main outcome was AD conversion from aMCI during follow-up. The EBM model was utilized to predict aMCI converting to AD based on three feature combinations, obtaining interpretability while ensuring accuracy. Meanwhile, the interaction effect was considered in the model. The three feature combinations were compared in different follow-up periods with accuracy, sensitivity, specificity, and AUC-ROC. The global and local explanations are displayed by importance ranking and feature interpretability plots. Results: The five-years prediction accuracy reached 85% (AUC = 0.92) using both cognitive scores and MRI markers. Apart from accuracies, we obtained features’ importance in different follow-up periods. In early stage of AD, the MRI markers play a major role, while for middle-term, the cognitive scores are more important. Feature risk scoring plots demonstrated insightful nonlinear interactive associations between selected factors and outcome. In one-year prediction, lower right inferior temporal volume (<9000) is significantly associated with AD conversion. For two-year prediction, low left inferior temporal thickness (<2) is most critical. For three-year prediction, higher FAQ scores (>4) is the most important. During four-year prediction, APOE4 is the most critical. For five-year prediction, lower right entorhinal volume (<1000) is the most critical feature. Conclusions: The established glass-box model EBMs with multimodal features demonstrated a superior ability with detailed interpretability in predicting AD conversion from MCI. Multi features with significant importance were identified. Further study may be of significance to determine whether the established prediction tool would improve clinical management for AD patients. Full article

The underlying genetic susceptibility for Alzheimer’s disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the disease. AD endophenotypes based on amyloid-β, tau, and neurodegeneration (A/T/N) biomarkers and cognitive performance were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). A genome-wide association study (GWAS) of quantitative phenotypes was performed using an SNP main effect and an SNP by Diagnosis interaction (SNP × DX) model to identify disease stage-specific genetic effects. Nine loci were identified as study-wide significant with one or more A/T/N endophenotypes in the main effect model, as well as additional findings significantly associated with cognitive measures. These nine loci include SNPs in or near the genes APOE, SRSF10, HLA-DQB1, XKR3, and KIAA1671. The SNP × DX model identified three study-wide significant genetic loci (BACH2, EP300, and PACRG-AS1) with a neuroprotective effect in later AD stage endophenotypes. An endophenotype approach identified novel genetic associations and provided insight into the molecular mechanisms underlying the genetic associations that may otherwise be missed using conventional case-control study designs. Full article

Early diagnosis of Alzheimer’s disease (AD) is an important task that facilitates the development of treatment and prevention strategies, and may potentially improve patient outcomes. Neuroimaging has shown great promise, including the amyloid-PET, which measures the accumulation of amyloid plaques in the brain—a hallmark of AD. It is desirable to train end-to-end deep learning models to predict the progression of AD for individuals at early stages based on 3D amyloid-PET. However, commonly used models are trained in a fully supervised learning manner, and they are inevitably biased toward the given label information. To this end, we propose a selfsupervised contrastive learning method to accurately predict the conversion to AD for individuals with mild cognitive impairment (MCI) with 3D amyloid-PET. The proposed method, SMoCo, uses both labeled and unlabeled data to capture general semantic representations underlying the images. As the downstream task is given as classification of converters vs. non-converters, unlike the general self-supervised learning problem that aims to generate task-agnostic representations, SMoCo additionally utilizes the label information in the pre-training. To demonstrate the performance of our method, we conducted experiments on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. The results confirmed that the proposed method is capable of providing appropriate data representations, resulting in accurate classification. SMoCo showed the best classification performance over the existing methods, with AUROC = 85.17%, accuracy = 81.09%, sensitivity = 77.39%, and specificity = 82.17%. While SSL has demonstrated great success in other application domains of computer vision, this study provided the initial investigation of using a proposed self-supervised contrastive learning model, SMoCo, to effectively predict MCI conversion to AD based on 3D amyloid-PET. Full article

In this article, some prescriptions to define a distribution on the set $Q_0$ of all rational numbers in $[0,1]$ are outlined. We explored a few properties of these distributions and the possibility of making these rational numbers asymptotically equiprobable in a suitable sense. In particular, it will be shown that in the said limit—albeit no absolutely continuous uniform distribution can be properly defined in ${\mathbb{Q}}_0$—the probability allotted to every single $q\in {\mathbb{Q}}_0$ asymptotically vanishes, while that of the subset of ${\mathbb{Q}}_0$ falling in an interval $[a,b]\subseteq {\mathbb{Q}}_0$ goes to $b-a$. We finally present some hints to complete sequencing without repeating the numbers in ${\mathbb{Q}}_0$ as a prerequisite to laying down more distributions on it. Full article