Identifying vulnerable brain networks associated with Alzheimer's disease risk.

The selective vulnerability of brain networks in individuals at risk for Alzheimer's disease (AD) may help differentiate pathological from normal aging at asymptomatic stages, allowing the implementation of more effective interventions. We used a sample of 72 people across the age span, enriched for the APOE4 genotype to reveal vulnerable networks associated with a composite AD risk factor including age, genotype, and sex. Sparse canonical correlation analysis (CCA) revealed a high weight associated with genotype, and subgraphs involving the cuneus, temporal, cingulate cortices, and cerebellum. Adding cognitive metrics to the risk factor revealed the highest cumulative degree of connectivity for the pericalcarine cortex, insula, banks of the superior sulcus, and the cerebellum. To enable scaling up our approach, we extended tensor network principal component analysis, introducing CCA components. We developed sparse regression predictive models with errors of 17% for genotype, 24% for family risk factor for AD, and 5 years for age. Age prediction in groups including cognitively impaired subjects revealed regions not found using only normal subjects, i.e. middle and transverse temporal, paracentral and superior banks of temporal sulcus, as well as the amygdala and parahippocampal gyrus. These modeling approaches represent stepping stones towards single subject prediction.

A Continuous Extension of Gene Set Enrichment Analysis Using the Likelihood Ratio Test Statistics Identifies Vascular Endothelial Growth Factor as a Candidate Pathway for Alzheimer's Disease via ITGA5.

BACKGROUND: Alzheimer's disease (AD) involves brain neuropathologies such as amyloid plaque and hyperphosphorylated tau tangles and is accompanied by cognitive decline. Identifying the biological mechanisms underlying disease onset and progression based on quantifiable phenotypes will help understand disease etiology and devise therapies. OBJECTIVE: Our objective was to identify molecular pathways associated with hallmark AD biomarkers and cognitive status, accounting for variables such as age, sex, education, and APOE genotype. METHODS: We introduce a pathway-based statistical approach, extending the gene set likelihood ratio test to continuous phenotypes. We first analyzed independently each of the three phenotypes (amyloid-ß, tau, cognition) using continuous gene set likelihood ratio tests to account for covariates, including age, sex, education, and APOE genotype. The analysis involved 634 subjects with data available for all three phenotypes, allowing for the identification of common pathways. RESULTS: We identified 14 pathways significantly associated with amyloid-ß; 5 associated with tau; and 174 associated with cognition, which showed a larger number of pathways compared to biomarkers. A single pathway, vascular endothelial growth factor receptor binding (VEGF-RB), exhibited associations with all three phenotypes. Mediation analysis showed that among the VEGF-RB family genes, ITGA5 mediates the relationship between cognitive scores and pathological biomarkers. CONCLUSIONS: We presented a new statistical approach linking continuous phenotypes, gene expression across pathways, and covariates like sex, age, and education. Our results reinforced VEGF RB2's role in AD cognition and demonstrated ITGA5's significant role in mediating the AD pathology-cognition connection.

Mapping the impact of age and APOE risk factors for late onset Alzheimer's disease on long range brain connections through multiscale bundle analysis.

Alzheimer's disease currently has no cure and is usually detected too late for interventions to be effective. In this study we have focused on cognitively normal subjects to study the impact of risk factors on their long-range brain connections. To detect vulnerable connections, we devised a multiscale, hierarchical method for spatial clustering of the whole brain tractogram and examined the impact of age and APOE allelic variation on cognitive abilities and bundle properties including texture e.g., mean fractional anisotropy, variability, and geometric properties including streamline length, volume, and shape, as well as asymmetry. We found that the third level subdivision in the bundle hierarchy provided the most sensitive ability to detect age and genotype differences associated with risk factors. Our results indicate that frontal bundles were a major age predictor, while the occipital cortex and cerebellar connections were important risk predictors that were heavily genotype dependent, and showed accelerated decline in fractional anisotropy, shape similarity, and increased asymmetry. Cognitive metrics related to olfactory memory were mapped to bundles, providing possible early markers of neurodegeneration. In addition, physiological metrics such as diastolic blood pressure were associated with changes in white matter tracts. Our novel method for a data driven analysis of sensitive changes in tractography may differentiate populations at risk for AD and isolate specific vulnerable networks.

APOE, Immune Factors, Sex, and Diet Interact to Shape Brain Networks in Mouse Models of Aging.

Alzheimer's disease (AD) presents complex challenges due to its multifactorial nature, poorly understood etiology, and late detection. The mechanisms through which genetic, fixed and modifiable risk factors influence susceptibility to AD are under intense investigation, yet the impact of unique risk factors on brain networks is difficult to disentangle, and their interactions remain unclear. To model multiple risk factors including APOE genotype, age, sex, diet, and immunity we leveraged mice expressing the human APOE and NOS2 genes, conferring a reduced immune response compared to mouse Nos2. Employing graph analyses of brain connectomes derived from accelerated diffusion-weighted MRI, we assessed the global and local impact of risk factors in the absence of AD pathology. Aging and a high-fat diet impacted extensive networks comprising AD-vulnerable regions, including the temporal association cortex, amygdala, and the periaqueductal gray, involved in stress responses. Sex impacted networks including sexually dimorphic regions (thalamus, insula, hypothalamus) and key memory-processing areas (fimbria, septum). APOE genotypes modulated connectivity in memory, sensory, and motor regions, while diet and immunity both impacted the insula and hypothalamus. Notably, these risk factors converged on a circuit comprising 63 of 54,946 total connections (0.11% of the connectome), highlighting shared vulnerability amongst multiple AD risk factors in regions essential for sensory integration, emotional regulation, decision making, motor coordination, memory, homeostasis, and interoception. These network-based biomarkers hold translational value for distinguishing high-risk versus low-risk participants at preclinical AD stages, suggest circuits as potential therapeutic targets, and advance our understanding of network fingerprints associated with AD risk. Significance Statement: Current interventions for Alzheimer's disease (AD) do not provide a cure, and are delivered years after neuropathological onset. Addressing the impact of risk factors on brain networks holds promises for early detection, prevention, and revealing putative therapeutic targets at preclinical stages. We utilized six mouse models to investigate the impact of factors, including APOE genotype, age, sex, immunity, and diet, on brain networks. Large structural connectomes were derived from high resolution compressed sensing diffusion MRI. A highly parallelized graph classification identified subnetworks associated with unique risk factors, revealing their network fingerprints, and a common network composed of 63 connections with shared vulnerability to all risk factors. APOE genotype specific immune signatures support the design of interventions tailored to risk profiles.

Multivariate investigation of aging in mouse models expressing the Alzheimer's protective APOE2 allele: integrating cognitive metrics, brain imaging, and blood transcriptomics.

APOE allelic variation is critical in brain aging and Alzheimer's disease (AD). The APOE2 allele associated with cognitive resilience and neuroprotection against AD remains understudied. We employed a multipronged approach to characterize the transition from middle to old age in mice with APOE2 allele, using behavioral assessments, image-derived morphometry and diffusion metrics, structural connectomics, and blood transcriptomics. We used sparse multiple canonical correlation analyses (SMCCA) for integrative modeling, and graph neural network predictions. Our results revealed brain sub-networks associated with biological traits, cognitive markers, and gene expression. The cingulate cortex emerged as a critical region, demonstrating age-associated atrophy and diffusion changes, with higher fractional anisotropy in males and middle-aged subjects. Somatosensory and olfactory regions were consistently highlighted, indicating age-related atrophy and sex differences. The hippocampus exhibited significant volumetric changes with age, with differences between males and females in CA3 and CA1 regions. SMCCA underscored changes in the cingulate cortex, somatosensory cortex, olfactory regions, and hippocampus in relation to cognition and blood-based gene expression. Our integrative modeling in aging APOE2 carriers revealed a central role for changes in gene pathways involved in localization and the negative regulation of cellular processes. Our results support an important role of the immune system and response to stress. This integrative approach offers novel insights into the complex interplay among brain connectivity, aging, and sex. Our study provides a foundation for understanding the impact of APOE2 allele on brain aging, the potential for detecting associated changes in blood markers, and revealing novel therapeutic intervention targets.

Accelerated Brain Atrophy, Microstructural Decline and Connectopathy in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) has recently been linked to cognitive impairment. We hypothesized that AMD modifies the brain aging trajectory, and we conducted a longitudinal diffusion MRI study on 40 participants (20 with AMD and 20 controls) to reveal the location, extent, and dynamics of AMD-related brain changes. Voxel-based analyses at the first visit identified reduced volume in AMD participants in the cuneate gyrus, associated with vision, and the temporal and bilateral cingulate gyrus, linked to higher cognition and memory. The second visit occurred 2 years after the first and revealed that AMD participants had reduced cingulate and superior frontal gyrus volumes, as well as lower fractional anisotropy (FA) for the bilateral occipital lobe, including the visual and the superior frontal cortex. We detected faster rates of volume and FA reduction in AMD participants in the left temporal cortex. We identified inter-lingual and lingual-cerebellar connections as important differentiators in AMD participants. Bundle analyses revealed that the lingual gyrus had a lower streamline length in the AMD participants at the first visit, indicating a connection between retinal and brain health. FA differences in select inter-lingual and lingual cerebellar bundles at the second visit showed downstream effects of vision loss. Our analyses revealed widespread changes in AMD participants, beyond brain networks directly involved in vision processing.

Correction: Multivariate functional group sparse regression: Functional predictor selection.

[This corrects the article DOI: 10.1371/journal.pone.0265940.].

A Continuous Extension of Gene Set Enrichment Analysis using the Likelihood Ratio Test Statistics Identifies VEGF as a Candidate Pathway for Alzheimer's disease.

Background: Alzheimer's disease involves brain pathologies such as amyloid plaque depositions and hyperphosphorylated tau tangles and is accompanied by cognitive decline. Identifying the biological mechanisms underlying disease onset and progression based on quantifiable phenotypes will help understand the disease etiology and devise therapies. Objective: Our objective was to identify molecular pathways associated with AD biomarkers (Amyloid-ß and tau) and cognitive status (MMSE) accounting for variables such as age, sex, education, and APOE genotype. Methods: We introduce a novel pathway-based statistical approach, extending the gene set likelihood ratio test to continuous phenotypes. We first analyzed independently each of the three phenotypes (Amyloid-ß, tau, cognition), using continuous gene set likelihood ratio tests to account for covariates, including age, sex, education, and APOE genotype. The analysis involved a large sample size with data available for all three phenotypes, allowing for the identification of common pathways. Results: We identified 14 pathways significantly associated with Amyloid-ß, 5 associated with tau, and 174 associated with MMSE. Surprisingly, the MMSE outcome showed a larger number of significant pathways compared to biomarkers. A single pathway, vascular endothelial growth factor receptor binding (VEGF-RB), exhibited significant associations with all three phenotypes. Conclusions: The study's findings highlight the importance of the VEGF signaling pathway in aging in AD. The complex interactions within the VEGF signaling family offer valuable insights for future therapeutic interventions.

Feature attention graph neural network for estimating brain age and identifying important neural connections in mouse models of genetic risk for Alzheimer's disease.

Alzheimer's disease (AD) remains one of the most extensively researched neurodegenerative disorders due to its widespread prevalence and complex risk factors. Age is a crucial risk factor for AD, which can be estimated by the disparity between physiological age and estimated brain age. To model AD risk more effectively, integrating biological, genetic, and cognitive markers is essential. Here, we utilized mouse models expressing the major APOE human alleles and human nitric oxide synthase 2 to replicate genetic risk for AD and a humanized innate immune response. We estimated brain age employing a multivariate dataset that includes brain connectomes, APOE genotype, subject traits such as age and sex, and behavioral data. Our methodology used Feature Attention Graph Neural Networks (FAGNN) for integrating different data types. Behavioral data were processed with a 2D Convolutional Neural Network (CNN), subject traits with a 1D CNN, brain connectomes through a Graph Neural Network using quadrant attention module. The model yielded a mean absolute error for age prediction of 31.85 days, with a root mean squared error of 41.84 days, outperforming other, reduced models. In addition, FAGNN identified key brain connections involved in the aging process. The highest weights were assigned to the connections between cingulum and corpus callosum, striatum, hippocampus, thalamus, hypothalamus, cerebellum, and piriform cortex. Our study demonstrates the feasibility of predicting brain age in models of aging and genetic risk for AD. To verify the validity of our findings, we compared Fractional Anisotropy (FA) along the tracts of regions with the highest connectivity, the Return-to-Origin Probability (RTOP), Return-to-Plane Probability (RTPP), and Return-to-Axis Probability (RTAP), which showed significant differences between young, middle-aged, and old age groups. Younger mice exhibited higher FA, RTOP, RTAP, and RTPP compared to older groups in the selected connections, suggesting that degradation of white matter tracts plays a critical role in aging and for FAGNN's selections. Our analysis suggests a potential neuroprotective role of APOE2, relative to APOE3 and APOE4, where APOE2 appears to mitigate age-related changes. Our findings highlighted a complex interplay of genetics and brain aging in the context of AD risk modeling.

Advanced photon counting CT imaging pipeline for cardiac phenotyping of apolipoprotein E mouse models.

BACKGROUND: Cardiovascular disease (CVD) is associated with the apolipoprotein E (APOE) gene and lipid metabolism. This study aimed to develop an imaging-based pipeline to comprehensively assess cardiac structure and function in mouse models expressing different APOE genotypes using photon-counting computed tomography (PCCT). METHODS: 123 mice grouped based on APOE genotype (APOE2, APOE3, APOE4, APOE knockout (KO)), gender, human NOS2 factor, and diet (control or high fat) were used in this study. The pipeline included PCCT imaging on a custom-built system with contrast-enhanced in vivo imaging and intrinsic cardiac gating, spectral and temporal iterative reconstruction, spectral decomposition, and deep learning cardiac segmentation. Statistical analysis evaluated genotype, diet, sex, and body weight effects on cardiac measurements. RESULTS: Our results showed that PCCT offered high quality imaging with reduced noise. Material decomposition enabled separation of calcified plaques from iodine enhanced blood in APOE KO mice. Deep learning-based segmentation showed good performance with Dice scores of 0.91 for CT-based segmentation and 0.89 for iodine map-based segmentation. Genotype-specific differences were observed in left ventricular volumes, heart rate, stroke volume, ejection fraction, and cardiac index. Statistically significant differences were found between control and high fat diets for APOE2 and APOE4 genotypes in heart rate and stroke volume. Sex and weight were also significant predictors of cardiac measurements. The inclusion of the human NOS2 gene modulated these effects. CONCLUSIONS: This study demonstrates the potential of PCCT in assessing cardiac structure and function in mouse models of CVD which can help in understanding the interplay between genetic factors, diet, and cardiovascular health.

Multivariate functional group sparse regression: Functional predictor selection.

In this paper, we propose methods for functional predictor selection and the estimation of smooth functional coefficients simultaneously in a scalar-on-function regression problem under a high-dimensional multivariate functional data setting. In particular, we develop two methods for functional group-sparse regression under a generic Hilbert space of infinite dimension. We show the convergence of algorithms and the consistency of the estimation and the selection (oracle property) under infinite-dimensional Hilbert spaces. Simulation studies show the effectiveness of the methods in both the selection and the estimation of functional coefficients. The applications to functional magnetic resonance imaging (fMRI) reveal the regions of the human brain related to ADHD and IQ.

Automated multimodal segmentation of acute ischemic stroke lesions on clinical MR images.

Magnetic resonance (MR) imaging (MRI) is commonly used to diagnose, assess and monitor stroke. Accurate and timely segmentation of stroke lesions provides the anatomico-structural information that can aid physicians in predicting prognosis, as well as in decision making and triaging for various rehabilitation strategies. To segment stroke lesions, MR protocols, including diffusion-weighted imaging (DWI) and T2-weighted fluid attenuated inversion recovery (FLAIR) are often utilized. These imaging sequences are usually acquired with different spatial resolutions due to time constraints. Within the same image, voxels may be anisotropic, with reduced resolution along slice direction for diffusion scans in particular. In this study, we evaluate the ability of 2D and 3D U-Net Convolutional Neural Network (CNN) architectures to segment ischemic stroke lesions using single contrast (DWI) and dual contrast images (T2w FLAIR and DWI). The predicted segmentations correlate with post-stroke motor outcome measured by the National Institutes of Health Stroke Scale (NIHSS) and Fugl-Meyer Upper Extremity (FM-UE) index based on the lesion loads overlapping the corticospinal tracts (CST), which is a neural substrate for motor movement and function. Although the four methods performed similarly, the 2D multimodal U-Net achieved the best results with a mean Dice of 0.737 (95% CI: 0.705, 0.769) and a relatively high correlation between the weighted lesion load and the NIHSS scores (both at baseline and at 90 days). A monotonically constrained quintic polynomial regression yielded R2 = 0.784 and 0.875 for weighted lesion load versus baseline and 90-Days NIHSS respectively, and better corrected Akaike information criterion (AICc) scores than those of the linear regression. In addition, using the quintic polynomial regression model to regress the weighted lesion load to the 90-Days FM-UE score results in an R2 of 0.570 with a better AICc score than that of the linear regression. Our results suggest that the multi-contrast information enhanced the accuracy of the segmentation and the prediction accuracy for upper extremity motor outcomes. Expanding the training dataset to include different types of stroke lesions and more data points will help add a temporal longitudinal aspect and increase the accuracy. Furthermore, adding patient-specific data may improve the inference about the relationship between imaging metrics and functional outcomes.