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.

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.

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.

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.

A tissue-fraction estimation-based segmentation method for quantitative dopamine transporter SPECT.

BACKGROUND: Quantitative measures of dopamine transporter (DaT) uptake in caudate, putamen, and globus pallidus (GP) derived from dopamine transporter-single-photon emission computed tomography (DaT-SPECT) images have potential as biomarkers for measuring the severity of Parkinson's disease. Reliable quantification of this uptake requires accurate segmentation of the considered regions. However, segmentation of these regions from DaT-SPECT images is challenging, a major reason being partial-volume effects (PVEs) in SPECT. The PVEs arise from two sources, namely the limited system resolution and reconstruction of images over finite-sized voxel grids. The limited system resolution results in blurred boundaries of the different regions. The finite voxel size leads to TFEs, that is, voxels contain a mixture of regions. Thus, there is an important need for methods that can account for the PVEs, including the TFEs, and accurately segment the caudate, putamen, and GP, from DaT-SPECT images. PURPOSE: Design and objectively evaluate a fully automated tissue-fraction estimation-based segmentation method that segments the caudate, putamen, and GP from DaT-SPECT images. METHODS: The proposed method estimates the posterior mean of the fractional volumes occupied by the caudate, putamen, and GP within each voxel of a three-dimensional DaT-SPECT image. The estimate is obtained by minimizing a cost function based on the binary cross-entropy loss between the true and estimated fractional volumes over a population of SPECT images, where the distribution of true fractional volumes is obtained from existing populations of clinical magnetic resonance images. The method is implemented using a supervised deep-learning-based approach. RESULTS: Evaluations using clinically guided highly realistic simulation studies show that the proposed method accurately segmented the caudate, putamen, and GP with high mean Dice similarity coefficients of ∼ 0.80 and significantly outperformed ( p < 0.01 $p < 0.01$ ) all other considered segmentation methods. Further, an objective evaluation of the proposed method on the task of quantifying regional uptake shows that the method yielded reliable quantification with low ensemble normalized root mean square error (NRMSE) < 20% for all the considered regions. In particular, the method yielded an even lower ensemble NRMSE of ∼ 10% for the caudate and putamen. CONCLUSIONS: The proposed tissue-fraction estimation-based segmentation method for DaT-SPECT images demonstrated the ability to accurately segment the caudate, putamen, and GP, and reliably quantify the uptake within these regions. The results motivate further evaluation of the method with physical-phantom and patient studies.