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Alzheimer’s disease (AD) is the most common form of dementia and results in neurodegeneration and cognitive impairment. White matter (WM) is affected in AD and has implications for neural circuitry and cognitive function. The trajectory of these changes across age, however, is still not well understood, especially at earlier stages in life. To address this, we used theApp^{NL-G-F/NL-G-F}knock-in (APPKI) mouse model that harbors a single copy knock-in of the human amyloid precursor protein (APP) gene with three familial AD mutations. We performedin vivodiffusion tensor imaging (DTI) to study how the structural properties of the brain change across age in the context of AD. In late age APPKI mice, we observed reduced fractional anisotropy (FA), a proxy of WM integrity, in multiple brain regions, including the hippocampus, anterior commissure (AC), neocortex, and hypothalamus. At the cellular level, we observed greater numbers of oligodendrocytes in middle age (prior to observations in DTI) in both the AC, a major interhemispheric WM tract, and the hippocampus, which is involved in memory and heavily affected in AD, prior to observations in DTI. Proteomics analysis of the hippocampus also revealed altered expression of oligodendrocyte-related proteins with age and in APPKI mice. Together, these results help to improve our understanding of the development of AD pathology with age, and imply that middle age may be an important temporal window for potential therapeutic intervention.

 

Introduction Alzheimer's disease (AD) is a progressive neurodegenerative disease. The early processes of AD, however, are not fully understood and likely begin years before symptoms manifest. Importantly, disruption of the default mode network, including the hippocampus, has been implicated in AD. Methods To examine the role of functional network connectivity changes in the early stages of AD, we performed resting-state functional magnetic resonance imaging (rs-fMRI) using a mouse model harboring three familial AD mutations ( App NL-G-F/NL-G-F knock-in, APPKI) in female mice in early, middle, and late age groups. The interhemispheric and intrahemispheric functional connectivity (FC) of the hippocampus was modeled across age. Results We observed higher interhemispheric functional connectivity (FC) in the hippocampus across age. This was reduced, however, in APPKI mice in later age. Further, we observed loss of hemispheric asymmetry in FC in APPKI mice. Discussion Together, this suggests that there are early changes in hippocampal FC prior to heavy onset of amyloid β plaques, and which may be clinically relevant as an early biomarker of AD. 

Brain networks have attracted increasing attention due to the potential to better characterize brain dynamics and abnormalities in neurological and psychiatric conditions. Recent years have witnessed enormous successes in deep learning. Many AI algorithms, especially graph learning methods, have been proposed to analyze brain networks. An important issue for existing graph learning methods is that those models are not typically easy to interpret. In this study, we proposed an interpretable graph learning model for brain network regression analysis. We applied this new framework on the subjects from Human Connectome Project (HCP) for predicting multiple Adult Self-Report (ASR) scores. We also use one of the ASR scores as the example to demonstrate how to identify sex differences in the regression process using our model. In comparison with other state-of-the-art methods, our results clearly demonstrate the superiority of our new model in effectiveness, fairness, and transparency. 

Understanding the modularity of functional magnetic resonance imaging (fMRI)–derived brain networks or “connectomes” can inform the study of brain function organization. However, fMRI connectomes additionally involve negative edges, which may not be optimally accounted for by existing approaches to modularity that variably threshold, binarize, or arbitrarily weight these connections. Consequently, many existingQmaximization‐based modularity algorithms yield variable modular structures. Here, we present an alternative complementary approach that exploits how frequent the blood–oxygen–level–dependent (BOLD) signal correlation between two nodes is negative. We validated this novel probability‐based modularity approach on two independent publicly‐available resting‐state connectome data sets (the Human Connectome Project [HCP] and the 1,000 functional connectomes) and demonstrated that negative correlations alone are sufficient in understanding resting‐state modularity. In fact, this approach (a) permits a dual formulation, leading to equivalent solutions regardless of whether one considers positive or negative edges; (b) is theoretically linked to the Ising model defined on the connectome, thus yielding modularity result that maximizes data likelihood. Additionally, we were able to detect novel and consistent sex differences in modularity in both data sets. As data sets like HCP become widely available for analysis by the neuroscience community at large, alternative and perhaps more advantageous computational tools to understand the neurobiological information of negative edges in fMRI connectomes are increasingly important.