Effect of APOE ε4 on multimodal brain connectomic traits: a persistent homology study.

BACKGROUND: Although genetic risk factors and network-level neuroimaging abnormalities have shown effects on cognitive performance and brain atrophy in Alzheimer's disease (AD), little is understood about how apolipoprotein E (APOE) ε4 allele, the best-known genetic risk for AD, affect brain connectivity before the onset of symptomatic AD. This study aims to investigate APOE ε4 effects on brain connectivity from the perspective of multimodal connectome. RESULTS: Here, we propose a novel multimodal brain network modeling framework and a network quantification method based on persistent homology for identifying APOE ε4-related network differences. Specifically, we employ sparse representation to integrate multimodal brain network information derived from both the resting state functional magnetic resonance imaging (rs-fMRI) data and the diffusion-weighted magnetic resonance imaging (dw-MRI) data. Moreover, persistent homology is proposed to avoid the ad hoc selection of a specific regularization parameter and to capture valuable brain connectivity patterns from the topological perspective. The experimental results demonstrate that our method outperforms the competing methods, and reasonably yields connectomic patterns specific to APOE ε4 carriers and non-carriers. CONCLUSIONS: We have proposed a multimodal framework that integrates structural and functional connectivity information for constructing a fused brain network with greater discriminative power. Using persistent homology to extract topological features from the fused brain network, our method can effectively identify APOE ε4-related brain connectomic biomarkers.

Multivariate genome wide association and network analysis of subcortical imaging phenotypes in Alzheimer's disease.

BACKGROUND: Genome-wide association studies (GWAS) have identified many individual genes associated with brain imaging quantitative traits (QTs) in Alzheimer's disease (AD). However single marker level association discovery may not be able to address the underlying biological interactions with disease mechanism. RESULTS: In this paper, we used the MGAS (Multivariate Gene-based Association test by extended Simes procedure) tool to perform multivariate GWAS on eight AD-relevant subcortical imaging measures. We conducted multiple iPINBPA (integrative Protein-Interaction-Network-Based Pathway Analysis) network analyses on MGAS findings using protein-protein interaction (PPI) data, and identified five Consensus Modules (CMs) from the PPI network. Functional annotation and network analysis were performed on the identified CMs. The MGAS yielded significant hits within APOE, TOMM40 and APOC1 genes, which were known AD risk factors, as well as a few new genes such as LAMA1, XYLB, HSD17B7P2, and NPEPL1. The identified five CMs were enriched by biological processes related to disorders such as Alzheimer's disease, Legionellosis, Pertussis, and Serotonergic synapse. CONCLUSIONS: The statistical power of coupling MGAS with iPINBPA was higher than traditional GWAS method, and yielded new findings that were missed by GWAS. This study provides novel insights into the molecular mechanism of Alzheimer's Disease and will be of value to novel gene discovery and functional genomic studies.

Adversarially Trained Persistent Homology Based Graph Convolutional Network for Disease Identification Using Brain Connectivity.

Brain disease propagation is associated with characteristic alterations in the structural and functional connectivity networks of the brain. To identify disease-specific network representations, graph convolutional networks (GCNs) have been used because of their powerful graph embedding ability to characterize the non-Euclidean structure of brain networks. However, existing GCNs generally focus on learning the discriminative region of interest (ROI) features, often ignoring important topological information that enables the integration of connectome patterns of brain activity. In addition, most methods fail to consider the vulnerability of GCNs to perturbations in network properties of the brain, which considerably degrades the reliability of diagnosis results. In this study, we propose an adversarially trained persistent homology-based graph convolutional network (ATPGCN) to capture disease-specific brain connectome patterns and classify brain diseases. First, the brain functional/structural connectivity is constructed using different neuroimaging modalities. Then, we develop a novel strategy that concatenates the persistent homology features from a brain algebraic topology analysis with readout features of the global pooling layer of a GCN model to collaboratively learn the individual-level representation. Finally, we simulate the adversarial perturbations by targeting the risk ROIs from clinical prior, and incorporate them into a training loop to evaluate the robustness of the model. The experimental results on three independent datasets demonstrate that ATPGCN outperforms existing classification methods in disease identification and is robust to minor perturbations in network architecture. Our code is available at https://github.com/CYB08/ATPGCN.

Multi-Modal Neuroimaging Neural Network-Based Feature Detection for Diagnosis of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative brain disease, and it is challenging to mine features that distinguish AD and healthy control (HC) from multiple datasets. Brain network modeling technology in AD using single-modal images often lacks supplementary information regarding multi-source resolution and has poor spatiotemporal sensitivity. In this study, we proposed a novel multi-modal LassoNet framework with a neural network for AD-related feature detection and classification. Specifically, data including two modalities of resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) were adopted for predicting pathological brain areas related to AD. The results of 10 repeated experiments and validation experiments in three groups prove that our proposed framework outperforms well in classification performance, generalization, and reproducibility. Also, we found discriminative brain regions, such as Hippocampus, Frontal_Inf_Orb_L, Parietal_Sup_L, Putamen_L, Fusiform_R, etc. These discoveries provide a novel method for AD research, and the experimental study demonstrates that the framework will further improve our understanding of the mechanisms underlying the development of AD.

Multi-dimensional persistent feature analysis identifies connectivity patterns of resting-state brain networks in Alzheimer's disease.

Objective.The characterization of functional brain network is crucial to understanding the neural mechanisms associated with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Some studies have shown that graph theoretical analysis could reveal changes of the disease-related brain networks by thresholding edge weights. But the choice of threshold depends on ambiguous cognitive conditions, which leads to the lack of interpretability. Recently, persistent homology (PH) was proposed to record the persistence of topological features of networks across every possible thresholds, reporting a higher sensitivity than graph theoretical features in detecting network-level biomarkers of AD. However, most research on PH focused on zero-dimensional features (persistence of connected components) reflecting the intrinsic topology of the brain network, rather than one-dimensional features (persistence of cycles) with an interesting neurobiological communication pattern. Our aim is to explore the multi-dimensional persistent features of brain networks in the AD and MCI patients, and further to capture valuable brain connectivity patterns.Approach.We characterized the change rate of the connected component numbers across graph filtration using the functional derivative curves, and examined the persistence landscapes that vectorize the persistence of cycle structures. After that, the multi-dimensional persistent features were validated in disease identification using a K-nearest neighbor algorithm. Furthermore, a connectivity pattern mining framework was designed to capture the disease-specific brain structures.Main results.We found that the multi-dimensional persistent features can identify statistical group differences, quantify subject-level distances, and yield disease-specific connectivity patterns. Relatively high classification accuracies were received when compared with graph theoretical features.Significance.This work represents a conceptual bridge linking complex brain network analysis and computational topology. Our results can be beneficial for providing a complementary objective opinion to the clinical diagnosis of neurodegenerative diseases.

Persistent Feature Analysis of Multimodal Brain Networks Using Generalized Fused Lasso for EMCI Identification.

Early Mild Cognitive Impairment (EMCI) involves very subtle changes in brain pathological process, and thus identification of EMCI can be challenging. By jointly analyzing cross-information among different neuroimaging data, an increased interest recently emerges in multimodal fusion to better understand clinical measurements with respect to both structural and functional connectivity. In this paper, we propose a novel multimodal brain network modeling method for EMCI identification. Specifically, we employ the structural connectivity based on diffusion tensor imaging (DTI), as a constraint, to guide the regression of BOLD time series from resting state functional magnetic resonance imaging (rs-fMRI). In addition, we introduce multiscale persistent homology features to avoid the uncertainty of regularization parameter selection. An empirical study on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database demonstrates that the proposed method effectively improves classification performance compared with several competing approaches, and reasonably yields connectivity patterns specific to different diagnostic groups.