Inducing Vascular Grammars for Anomaly Classification in Brain Angiograms

As machine learning is used to make strides in med- ical diagnostics, few methods provide heuristics from which human doctors can learn directly. This work introduces a method for leveraging human observable structures, such as macro scale vascular formations, for producing assessments of medical conditions with rela- tively few training cases, and uncovering patterns that are potential diagnostic aids. The approach draws on shape grammars, a rule-based technique, pioneered in design and architecture, and accelerated through a re- cursive sub-graph mining algorithm. The distribution of rule instances in the data from which they are in- duced is then used as an intermediary representation en- abling common classification and anomaly detection ap- proaches to identify indicative rules with relatively small data sets. The method is applied to 7 Tesla time-of- flight (TOF) angiography MRI (n = 54) of human brain vasculature. The data were segmented and induced to generate representative grammar rules. Ensembles of rules were isolated to implicate vascular conditions reli- ably. This application demonstrates the power of auto- mated structured intermediary representations for as- sessing nuanced biological form relationships, and the strength of shape grammars, in particular for identify- ing indicative patterns in complex vascular networks.

Argonaute-2 protects the neurovascular unit from damage caused by systemic inflammation

Background The brain vasculature plays a pivotal role in the inflammatory process by modulating the interaction between blood cells and the neurovascular unit. Argonaute-2 (Ago2) has been suggested as essential for endothelial survival but its role in the brain vasculature or in the endothelial–glial crosstalk has not been addressed. Thus, our aim was to clarify the significance of Ago2 in the inflammatory responses elicited by these cell types. Methods Mouse primary cultures of brain endothelial cells, astrocytes and microglia were used to evaluate cellular responses to the modulation of Ago2. Exposure of microglia to endothelial cell-conditioned media was used to assess the potential for in vivo studies. Adult mice were injected intraperitoneally with lipopolysaccharide (LPS) (2 mg/kg) followed by three daily intraperitoneal injections of Ago2 (0.4 nM) to assess markers of endothelial disruption, glial reactivity and neuronal function. Results Herein, we demonstrated that LPS activation disturbed the integrity of adherens junctions and downregulated Ago2 in primary brain endothelial cells. Exogenous treatment recovered intracellular Ago2 above control levels and recuperated vascular endothelial-cadherin expression, while downregulating LPS-induced nitric oxide release. Primary astrocytes did not show a significant change in Ago2 levels or response to the modulation of the Ago2 system, although endogenous Ago2 was shown to be critical in the maintenance of tumor necrosis factor-α basal levels. LPS-activated primary microglia overexpressed Ago2, and Ago2 silencing contained the inflammatory response to some extent, preventing interleukin-6 and nitric oxide release. Moreover, the secretome of Ago2-modulated brain endothelial cells had a protective effect over microglia. The intraperitoneal injection of LPS impaired blood–brain barrier and neuronal function, while triggering inflammation, and the subsequent systemic administration of Ago2 reduced or normalized endothelial, glial and neuronal markers of LPS damage. This outcome likely resulted from the direct action of Ago2 over the brain endothelium, which reestablished glial and neuronal function. Conclusions Ago2 could be regarded as a putative therapeutic agent, or target, in the recuperation of the neurovascular unit in inflammatory conditions.

Leukocyte - Cerebral Endothelial Cell Interactions in the Brain Lead to Anxiety-like Behaviour in Experimental Colitis

BACKGROUNDBehavioral comorbidities, such as anxiety and depression, are a prominent feature of IBD. The signals from the inflamed gut that cause changes in the brain leading to these behavioral comorbidities remain to be fully elucidated. We tested the hypothesis that enhanced leukocyte - cerebral endothelial cell interactions in experimental colitis initiate neuroimmune activation leading to anxiety-like behaviour.METHODSMale and female mice treated with dextran sodium sulfate were studied at the peak of acute colitis. Circulating leukocyte populations were determined using flow cytometry. Leukocyte - cerebral endothelial cell interactions were examined using intravital microscopy in mice treated with anti-integrin antibodies. Brain cytokine and chemokines were assessed using a multiplex assay in animals treated with anti-α4β7 integrin. Anxiety-like behavior was assessed using an elevated plus maze in animals after treatment with an intracerebroventricular injection of interleukin 1 receptor antagonist. RESULTSThe proportion of classical monocytes expressing α4β7 integrin was increased in peripheral blood of mice with colitis. An increase in the number of rolling and adherent leukocytes on cerebral endothelial cells was observed, the majority of which were neutrophils. Treatment with anti-α4β7 integrin significantly reduced the number of rolling leukocytes. After anti-Ly6C treatment to deplete monocytes, the number of rolling and adhering neutrophils were significantly reduced in mice with colitis. Interleukin-1β levels were elevated in the brain and treatment with anti-α4β7 significantly reduced them. Enhanced anxiety-like behaviour in mice with colitis was reversed by treatment with interleukin 1 receptor antagonist. CONCLUSIONSα4β7 integrin expressing monocytes direct the recruitment of neutrophils to the brain vasculature, leading to elevated cytokine levels that mediate anxiety-like behaviour in experimental colitis.

Subclinical Cardiac Dysfunction and Cognitive Function: A Systematic Review

Background Cardiovascular disease, and more recently, subclinical cardiac dysfunction have both been implicated as important risk factors for cognitive decline. Several measures have been used to detect subclinical cardiac dysfunction, with global longitudinal strain (GLS) emerging as an important and more sensitive indicator than traditional measures. Yet, the association of GLS with cognitive function remains relatively unexplored. Objective The aim of this review is to systematically summarize the literature exploring the association between GLS and cognitive function. Methods We conducted a systematic review of the literature following PRISMA guidelines using the following databases: PubMed, OVID Medline, Embase, Web of Science, and CINAHL. Inclusion criteria were observational studies published in English, measuring GLS and assessing cognitive function through neuropsychiatric tests or brain imaging. Quality assessment was done using the Newcastle Ottawa Scale. Results The initial search revealed 394 studies, of which three met inclusion criteria and were included for final review. The three studies included were cross-sectional and of high quality. They all reported that lower GLS scores were associated? with worse cognitive function and more brain abnormalities in both bivariate and multivariable analysis. Conclusion Subclinical cardiac dysfunction, identified by GLS, was associated with worse cognitive function and presence of cerebral abnormality on brain imaging. The underlying mechanism could be attributed to dysfunctional autoregulatory and microvascular processes occurring in the brain vasculature. Further longitudinal studies are needed to better delineate the relationship between GLS and cognitive function.

Characterization and tissue localization of zebrafish homologs of the human ABCB1 multidrug transporter

Capillary endothelial cells of the human blood–brain barrier (BBB) express high levels of P-glycoprotein (P-gp, encoded by ABCB1) and ABCG2 (encoded by ABCG2). However, little information is available regarding ATP-binding cassette transporters expressed at the zebrafish BBB, which has emerged as a potential model system. We report the characterization and tissue localization of two genes that are similar to ABCB1, zebrafish abcb4 and abcb5. When stably expressed in HEK293 cells, both Abcb4 and Abcb5 conferred resistance to P-gp substrates; however, Abcb5 poorly transported doxorubicin and mitoxantrone compared to zebrafish Abcb4. Additionally, Abcb5 did not transport the fluorescent P-gp probes BODIPY-ethylenediamine or LDS 751, while they were transported by Abcb4. High-throughput screening of 90 human P-gp substrates confirmed that Abcb4 has an overlapping substrate specificity profile with P-gp. In the brain vasculature, RNAscope probes for abcb4 colocalized with staining by the P-gp antibody C219, while abcb5 was not detected. The abcb4 probe also colocalized with claudin-5 in brain endothelial cells. Abcb4 and Abcb5 had different tissue localizations in multiple zebrafish tissues, potentially indicating different functions. The data suggest that zebrafish Abcb4 functionally phenocopies P-gp and that the zebrafish may serve as a model to study the role of P-gp at the BBB.

Combination of human endothelial colony-forming cells and mesenchymal stromal cells exert neuroprotective effects in the growth-restricted newborn

The foetal brain is particularly vulnerable to the detrimental effects of foetal growth restriction (FGR) with subsequent abnormal neurodevelopment being common. There are no current treatments to protect the FGR newborn from lifelong neurological disorders. This study examines whether pure foetal mesenchymal stromal cells (MSC) and endothelial colony-forming cells (ECFC) from the human term placenta are neuroprotective through modulating neuroinflammation and supporting the brain vasculature. We determined that one dose of combined MSC-ECFCs (cECFC; 106 ECFC 106 MSC) on the first day of life to the newborn FGR piglet improved damaged vasculature, restored the neurovascular unit, reduced brain inflammation and improved adverse neuronal and white matter changes present in the FGR newborn piglet brain. These findings could not be reproduced using MSCs alone. These results demonstrate cECFC treatment exerts beneficial effects on multiple cellular components in the FGR brain and may act as a neuroprotectant.

COVID-19 induces neuroinflammation and loss of hippocampal neurogenesis

Infection with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is associated with onset of neurological and psychiatric symptoms during and after the acute phase of illness1-4. Acute SARS-CoV-2 disease (COVID-19) presents with deficits of memory, attention, movement coordination, and mood. The mechanisms of these central nervous system symptoms remain largely unknown.In an established hamster model of intranasal infection with SARS-CoV-25, and patients deceased from COVID-19, we report a lack of viral neuroinvasion despite aberrant BBB permeability, microglial activation, and brain expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the inferior olivary nucleus of the medulla, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uremia or trauma. In the hippocampus dentate gyrus of both COVID-19 hamsters and humans, fewer cells expressed doublecortin, a marker of neuroblasts and immature neurons.Despite absence of viral neurotropism, we find SARS-CoV-2-induced inflammation, and hypoxia in humans, affect brain regions essential for fine motor function, learning, memory, and emotional responses, and result in loss of adult hippocampal neurogenesis. Neuroinflammation could affect cognition and behaviour via disruption of brain vasculature integrity, neurotransmission, and neurogenesis, acute effects that may persist in COVID-19 survivors with long-COVID symptoms.

Spontaneous regression of a thrombosed cerebral arteriovenous malformation in a patient with a prothrombotic state associated with multiple myeloma: A case report and literature review

Background: Cerebral arteriovenous malformations (AVMs) are pathologic communications between veins and arteries of the brain vasculature. Its spontaneous regression is rare, and many factors have been described in the effort to explain this phenomenon, including a hypercoagulable state. Case Description: We present the case of a spontaneous unruptured AVM regression in a patient where thrombosis of the malformation was found, probably due to a prothrombotic state associated with multiple myeloma (MM). Conclusion: We aim to contribute to the study of this rare phenomenon, presenting the relationship between a hypercoagulable state caused by MM and the spontaneous AVM regression that has not been previously reported.

Molecular atlas of the human brain vasculature at the single-cell level

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains poorly understood. Here, we performed single-cell RNA sequencing of 599,215 freshly isolated endothelial, perivascular and other tissue-derived cells from 47 fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We uncover extensive molecular heterogeneity of healthy fetal and adult human brains and across eight vascular-dependent CNS pathologies including brain tumors and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict numerous endothelial-to-perivascular cell ligand-receptor crosstalk including immune-related and angiogenic pathways, thereby unraveling a central role for the endothelium within brain neurovascular unit signaling networks. Our single-cell brain atlas provides insight into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.