The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem ...tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Adequate supply of blood and structural and functional integrity of blood vessels are key to normal brain functioning. On the other hand, cerebral blood flow shortfalls and blood-brain barrier ...dysfunction are early findings in neurodegenerative disorders in humans and animal models. Here we first examine molecular definition of cerebral blood vessels, as well as pathways regulating cerebral blood flow and blood-brain barrier integrity. Then we examine the role of cerebral blood flow and blood-brain barrier in the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. We focus on Alzheimer's disease as a platform of our analysis because more is known about neurovascular dysfunction in this disease than in other neurodegenerative disorders. Finally, we propose a hypothetical model of Alzheimer's disease biomarkers to include brain vasculature as a factor contributing to the disease onset and progression, and we suggest a common pathway linking brain vascular contributions to neurodegeneration in multiple neurodegenerative disorders.
Purpose
To develop a new 3D generative adversarial network that is designed and optimized for the application of multimodal 3D neuroimaging synthesis.
Methods
We present a 3D conditional generative ...adversarial network (GAN) that uses spectral normalization and feature matching to stabilize the training process and ensure optimization convergence (called SC‐GAN). A self‐attention module was also added to model the relationships between widely separated image voxels. The performance of the network was evaluated on the data set from ADNI‐3, in which the proposed network was used to predict PET images, fractional anisotropy, and mean diffusivity maps from multimodal MRI. Then, SC‐GAN was applied on a multidimensional diffusion MRI experiment for superresolution application. Experiment results were evaluated by normalized RMS error, peak SNR, and structural similarity.
Results
In general, SC‐GAN outperformed other state‐of‐the‐art GAN networks including 3D conditional GAN in all three tasks across all evaluation metrics. Prediction error of the SC‐GAN was 18%, 24% and 29% lower compared to 2D conditional GAN for fractional anisotropy, PET and mean diffusivity tasks, respectively. The ablation experiment showed that the major contributors to the improved performance of SC‐GAN are the adversarial learning and the self‐attention module, followed by the spectral normalization module. In the superresolution multidimensional diffusion experiment, SC‐GAN provided superior predication in comparison to 3D Unet and 3D conditional GAN.
Conclusion
In this work, an efficient end‐to‐end framework for multimodal 3D medical image synthesis (SC‐GAN) is presented. The source code is also made available at https://github.com/Haoyulance/SC‐GAN.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Numerous studies have examined the neuronal inputs and outputs of many areas within the mammalian cerebral cortex, but how these areas are organized into neural networks that communicate across the ...entire cortex is unclear. Over 600 labeled neuronal pathways acquired from tracer injections placed across the entire mouse neocortex enabled us to generate a cortical connectivity atlas. A total of 240 intracortical connections were manually reconstructed within a common neuroanatomic framework, forming a cortico-cortical connectivity map that facilitates comparison of connections from different cortical targets. Connectivity matrices were generated to provide an overview of all intracortical connections and subnetwork clusterings. The connectivity matrices and cortical map revealed that the entire cortex is organized into four somatic sensorimotor, two medial, and two lateral subnetworks that display unique topologies and can interact through select cortical areas. Together, these data provide a resource that can be used to further investigate cortical networks and their corresponding functions.
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•Imaging database of mouse cortical connectivity•Interactive cortical map allowing direct comparison of cortical projection data•Identification of topologically distinct cortical subnetworks•Insights into the connectivity architecture of the mouse neocortex
A comprehensive connectivity atlas of the murine cortex based on injections of neuronal tracers that collectively span the entire neocortex reveals hundreds of neural pathways and specific subnetworks with distinct topologies, providing a rich resource to frame experimental tests of functional connections.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The analysis of cerebral perivascular spaces (PVS) using magnetic resonance imaging (MRI) allows to explore in vivo their contributions to neurological disorders. To date the normal amount and ...distribution of PVS in healthy human brains are not known, thus hampering our ability to define with confidence pathogenic alterations. Furthermore, it is unclear which biological factors can influence the presence and size of PVS on MRI. We performed exploratory data analysis of PVS volume and distribution in a large population of healthy individuals (n = 897, age = 28.8 ± 3.7). Here we describe the global and regional amount of PVS in the white matter, which can be used as a reference for clinicians and researchers investigating PVS and may help the interpretation of the structural changes affecting PVS in pathological states. We found a relatively high inter-subject variability in the PVS amount in this population of healthy adults (range: 1.31–14.49 cm3). The PVS volume was higher in older and male individuals. Moreover, we identified body mass index, time of day, and genetics as new elements significantly affecting PVS in vivo under physiological conditions, offering a valuable foundation to future studies aimed at understanding the physiology of perivascular flow.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
White matter maturation is a nonlinear and heterogeneous phenomenon characterized by axonal packing, increased axon caliber, and a prolonged period of myelination. While current in vivo diffusion MRI ...(dMRI) methods, like diffusion tensor imaging (DTI), have successfully characterized the gross structure of major white matter tracts, these measures lack the specificity required to unravel the distinct processes that contribute to microstructural development. Neurite orientation dispersion and density imaging (NODDI) is a dMRI approach that probes tissue compartments and provides biologically meaningful measures that quantify neurite density index (NDI) and orientation dispersion index (ODI). The purpose of this study was to characterize the magnitude and timing of major white matter tract maturation with NODDI from infancy through adolescence in a cross-sectional cohort of 104 subjects (0.6–18.8 years). To probe the regional nature of white matter development, we use an along-tract approach that partitions tracts to enable more fine-grained analysis. Major white matter tracts showed exponential age-related changes in NDI with distinct maturational patterns. Overall, analyses revealed callosal fibers developed before association fibers. Our along-tract analyses elucidate spatially varying patterns of maturation with NDI that are distinct from those obtained with DTI. ODI was not significantly associated with age in the majority of tracts. Our results support the conclusion that white matter tract maturation is heterochronous process and, furthermore, we demonstrate regional variability in the developmental timing within major white matter tracts. Together, these results help to disentangle the distinct processes that contribute to and more specifically define the time course of white matter maturation.
•Neurite density index increases nonlinearly with age in major white matter tracts.•Callosal fibers develop earlier than association fibers using neurite density index.•Neurite density index rate of change varies along the length of tracts.•Orientation dispersion index is not related to age in the majority of tracts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
•PVS burden increases nonlinearly with age over the course of the lifespan.•PVS morphological trajectories differ in the white matter and basal ganglia.•Regions with low PVS burden in childhood ...undergo more rapid alterations in aging.•PVS volumetric expansion is fastest in temporal and occipital white matter.•Age-related variance in PVS volume is explained by sex and body mass index.
Enlarged perivascular spaces (PVS) are considered a biomarker for vascular pathology and are observed in normal aging and neurological conditions; however, research on the role of PVS in health and disease are hindered by the lack of knowledge regarding the normative time course of PVS alterations with age. To this end, we characterized the influence of age, sex and cognitive performance on PVS anatomical characteristics in a large cross-sectional cohort (∼1400) of healthy subjects between 8 and 90 years of age using multimodal structural MRI data. Our results show age is associated with wider and more numerous MRI-visible PVS over the course of the lifetime with spatially-varying patterns of PVS enlargement trajectories. In particular, regions with low PVS volume fraction in childhood are associated with rapid age-related PVS enlargement (e.g., temporal regions), while regions with high PVS volume fraction in childhood are associated with minimal age-related PVS alterations (e.g., limbic regions). PVS burden was significantly elevated in males compared to females with differing morphological time courses with age. Together, these findings contribute to our understanding of perivascular physiology across the healthy lifespan and provide a normative reference for the spatial distribution of PVS enlargement patterns to which pathological alterations can be compared.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although the systematic study of meditation is still in its infancy, research has provided evidence for meditation-induced improvements in psychological and physiological well-being. Moreover, ...meditation practice has been shown not only to benefit higher-order cognitive functions but also to alter brain activity. Nevertheless, little is known about possible links to brain structure. Using high-resolution MRI data of 44 subjects, we set out to examine the underlying anatomical correlates of long-term meditation with different regional specificity (i.e., global, regional, and local). For this purpose, we applied voxel-based morphometry in association with a recently validated automated parcellation approach. We detected significantly larger gray matter volumes in meditators in the right orbito-frontal cortex (as well as in the right thalamus and left inferior temporal gyrus when co-varying for age and/or lowering applied statistical thresholds). In addition, meditators showed significantly larger volumes of the right hippocampus. Both orbito-frontal and hippocampal regions have been implicated in emotional regulation and response control. Thus, larger volumes in these regions might account for meditators' singular abilities and habits to cultivate positive emotions, retain emotional stability, and engage in mindful behavior. We further suggest that these regional alterations in brain structures constitute part of the underlying neurological correlate of long-term meditation independent of a specific style and practice. Future longitudinal analyses are necessary to establish the presence and direction of a causal link between meditation practice and brain anatomy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Imaging the perivascular spaces (PVS), also known as Virchow-Robin space, has significant clinical value, but there remains a need for neuroimaging techniques to improve mapping and quantification of ...the PVS. Current technique for PVS evaluation is a scoring system based on visual reading of visible PVS in regions of interest, and often limited to large caliber PVS. Enhancing the visibility of the PVS could support medical diagnosis and enable novel neuroscientific investigations. Increasing the MRI resolution is one approach to enhance the visibility of PVS but is limited by acquisition time and physical constraints. Alternatively, image processing approaches can be utilized to improve the contrast ratio between PVS and surrounding tissue. Here we combine T1- and T2-weighted images to enhance PVS contrast, intensifying the visibility of PVS. The Enhanced PVS Contrast (EPC) was achieved by combining T1- and T2-weighted images that were adaptively filtered to remove non-structured high-frequency spatial noise. EPC was evaluated on healthy young adults by presenting them to two expert readers and also through automated quantification. We found that EPC improves the conspicuity of the PVS and aid resolving a larger number of PVS. We also present a highly reliable automated PVS quantification approach, which was optimized using expert readings.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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