Quantification of hypoxic regions distant from occlusions in cerebral penetrating arteriole trees

Xue, Yidan; Georgakopoulou, Theodosia; Wijk, A. van; Jozsa, T. I.; VanBavel, Ed; Payne, Stephen J.

doi:10.1371/journal.pcbi.1010166

Cited by 11 publications

(7 citation statements)

References 74 publications

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“…These findings raise the question of how can blocking a small fraction of capillaries (∼1.82-3.64% in diabetic mice), appreciably affect cognition? Although our stalling estimates are largely comprised of short-lived stalls lasting at least 6.5s, experimental and computational data suggest that 2-4% of stalled capillaries can lead to a 5-20% decrease in cerebral blood flow, which also improved cognition in Alzheimer mice 14, 82 . It is important to note that our microsphere experiments revealed that diabetes also increased the fraction of long-lived (∼3 day) capillary obstructions.…”

Section: Discussionmentioning

confidence: 99%

A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes

Sharma,

Cheema,

Tennant

et al. 2024

Preprint

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Vascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes, but precisely how capillary flow is affected and the underlying mechanisms remain elusive. Here we show that capillaries in the diabetic mouse brain are prone to stalling, with blocks composed primarily of erythrocyte plugs in branches off penetrating venules. Increased capillary obstructions were evident in both sexes and only partially reversed by insulin. Screening for circulating inflammatory cytokines revealed persistently high levels of interleukin-10 (IL-10) in diabetic mice. Contrary to expectation, stimulating IL-10 signalling increased capillary obstructions, whereas inhibiting IL-10 receptors with neutralizing antibodies or endothelial specific knockdown in diabetic mice, reversed these impairments. Chronic IL-10R blocking antibody treatment in diabetic mice also improved stimulus evoked cerebral blood flow, increased capillary widths in lower-order branches and reversed cognitive deficits. These data suggest IL-10 signalling plays an unexpected pathogenic role in cerebral microcirculatory defects and cognitive impairment.

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Section: Discussionmentioning

confidence: 99%

A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes

Sharma,

Cheema,

Tennant

et al. 2024

Preprint

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“…It thus also enables quantitative comparisons to be made between different conditions: for example, the study by Gkontra et al (2019), which, although in the porcine coronary microcirculation, showed that the measured permeability tensor dynamically changes in the seven days following myocardial infarction. Computational modelling in the cerebral circulation has also shown that the permeability changes in response to microthrombi (with the changes dependent upon the type of clot and the choice of thrombectomy procedure), El-Bouri et al (2021), and these changes have been recently validated in animal models, Xue et al (2021) and Xue et al (2022). Gaining a quantitative understanding of changes in the permeability tensor is a concise way of providing a better understanding of the response both to ischaemia and to therapies such as mechanical thrombectomy.…”

Section: Reconstruction Of the Microvasculaturementioning

confidence: 99%

Review of in silico models of cerebral blood flow in health and pathology

2023

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In this review, we provide a summary of the state-of-the-art in the in silico modelling of cerebral blood flow and its application in in silico clinical trials. Cerebral blood flow plays a key role in the transport of nutrients, including oxygen and glucose, to brain cells, and the cerebral vasculature is a highly complex, multi-scale, dynamic system that acts to ensure that supply and demand of these nutrients are continuously balanced. It also plays a key role in the transport of other substances, such as rt-PA, to brain tissue. Any dysfunction in cerebral blood flow can rapidly lead to cell death and permanent damage to brain regions, leading to loss of bodily functions and death.The complexity of the cerebral vasculature and the difficulty in obtaining accurate anatomical information combine to make mathematical models of cerebral blood flow key in understanding brain supply, diagnosis of cerebrovascular disease, selection of the optimum intervention, and neurosurgical planning. Similar in silico models have now been widely applied in other body organs, but models of cerebral blood flow lag far behind. The increased availability of experimental data in the last 15 years however has enabled these models to develop more rapidly and this progress is the focus of this review.We thus present a brief review of the cerebral vasculature and the mathematical foundations of cerebral blood flow. We demonstrate how such models can be applied in the context of cerebral diseases and show how this work has recently been expanded to in silico trials for the first time. Most work to date in this context has been performed for ischaemic stroke or cerebral aneurysms, but in-silico models have many other applications in neurodegenerative diseases where mathematical models have a vital role to play in testing hypotheses and providing test beds for clinical interventions.

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“…The model has been utilised for the simulation of brain osmotherapy and haemorrhagic transformation after stroke and validated with clinical data [33,34]. The present study sets out to extend computational brain models developed in the In Silico Clinical Trials for the Treatment of Acute Ischaemic Stroke (INSIST) project [28,[35][36][37] by incorporating a contact mechanics solver to simulate oedema with large deformations and ventricle collapse and then to investigate factors such as patient brain geometry, the severity of BBB damage and types of oedemas that can affect the ICP-MLS relation. Once a reliable model is established, it will help to sharpen the focus of resource-intensive clinical studies, and thus lower the associated (often very high) costs.…”

Section: Plos Computational Biologymentioning

confidence: 99%

Modelling midline shift and ventricle collapse in cerebral oedema following acute ischaemic stroke

Chen,

Józsa,

Cardim

et al. 2024

PLoS Comput Biol

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In ischaemic stroke, a large reduction in blood supply can lead to the breakdown of the blood-brain barrier and to cerebral oedema after reperfusion therapy. The resulting fluid accumulation in the brain may contribute to a significant rise in intracranial pressure (ICP) and tissue deformation. Changes in the level of ICP are essential for clinical decision-making and therapeutic strategies. However, the measurement of ICP is constrained by clinical techniques and obtaining the exact values of the ICP has proven challenging. In this study, we propose the first computational model for the simulation of cerebral oedema following acute ischaemic stroke for the investigation of ICP and midline shift (MLS) relationship. The model consists of three components for the simulation of healthy blood flow, occluded blood flow and oedema, respectively. The healthy and occluded blood flow components are utilized to obtain oedema core geometry and then imported into the oedema model for the simulation of oedema growth. The simulation results of the model are compared with clinical data from 97 traumatic brain injury patients for the validation of major model parameters. Midline shift has been widely used for the diagnosis, clinical decision-making, and prognosis of oedema patients. Therefore, we focus on quantifying the relationship between ICP and midline shift (MLS) and identify the factors that can affect the ICP-MLS relationship. Three major factors are investigated, including the brain geometry, blood-brain barrier damage severity and the types of oedema (including rare types of oedema). Meanwhile, the two major types (stress and tension/compression) of mechanical brain damage are also presented and the differences in the stress, tension, and compression between the intraparenchymal and periventricular regions are discussed. This work helps to predict ICP precisely and therefore provides improved clinical guidance for the treatment of brain oedema.

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Quantification of hypoxic regions distant from occlusions in cerebral penetrating arteriole trees

Cited by 11 publications

References 74 publications

A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes

A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes

Review of in silico models of cerebral blood flow in health and pathology

Modelling midline shift and ventricle collapse in cerebral oedema following acute ischaemic stroke

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