Compromised Blood-brain Barrier Research Articles

The protective effect of low-dose minocycline on brain microvascular ultrastructure in a rodent model of subarachnoid hemorrhage

The multifaceted nature of subarachnoid hemorrhage (SAH) pathogenesis is poorly understood. To date, no pharmacological agent has been found to be efficacious for the prevention of brain injury when used for acute SAH intervention. This study was undertaken to evaluate the beneficial effects of low-dose neuroprotective agent minocycline on brain microvascular ultrastructures that have not been studied in detail. We studied SAH brain injury using an in vivo prechiasmatic subarachnoid hemorrhage rodent model. We analyzed the qualitative and quantitative ultrastructural morphology of capillaries and surrounding neuropil in the rodent brains with SAH and/or minocycline administration. Here, we report that low-dose minocycline (1 mg/kg) displayed protective effects on capillaries and surrounding cells from significant SAH-induced changes. Ultrastructural morphology analysis revealed also that minocycline stopped endothelial cells from abnormal production of vacuoles and vesicles that compromise blood–brain barrier (BBB) transcellular transport. The reported ultrastructural abnormalities as well as neuroprotective effects of minocycline during SAH were not directly mediated by inhibition of MMP-2, MMP-9, or EMMPRIN. However, SAH brain tissue treated with minocycline was protected from development of other morphological features associated with oxidative stress and the presence of immune cells in the perivascular space. These data advance the knowledge on the effect of SAH on brain tissue ultrastructure in an SAH rodent model and the neuroprotective effect of minocycline when administered in low doses.

The Impairment of Blood-Brain Barrier in Alzheimer's Disease: Challenges and Opportunities with Stem Cells.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and its prevalence is increasing. Nowadays, very few drugs effectively reduce AD symptoms and thus, a better understanding of its pathophysiology is vital to design new effective schemes. Presymptomatic neuronal damage caused by the accumulation of Amyloid β peptide and Tau protein abnormalities remains a challenge, despite recent efforts in drug development. Importantly, therapeutic targets, biomarkers, and diagnostic techniques have emerged to detect and treat AD. Of note, the compromised blood-brain barrier (BBB) and peripheral inflammation in AD are becoming more evident, being harmful factors that contribute to the development of the disease. Perspectives from different pre-clinical and clinical studies link peripheral inflammation with the onset and progression of AD. This review aims to analyze the main factors and the contribution of impaired BBB in AD development. Additionally, we describe the potential therapeutic strategies using stem cells for AD treatment.

MPR-Specific Actions Influence Maintenance of the Blood-Brain Barrier (BBB).

Cerebral cavernous malformations (CCMs) are characterized by abnormally dilated intracranial microvascular sinusoids that result in increased susceptibility to hemorrhagic stroke. It has been demonstrated that three CCM proteins (CCM1, CCM2, and CCM3) form the CCM signaling complex (CSC) to mediate angiogenic signaling. Disruption of the CSC will result in hemorrhagic CCMs, a consequence of compromised blood–brain barrier (BBB) integrity. Due to their characteristically incomplete penetrance, the majority of CCM mutation carriers (presumed CCM patients) are largely asymptomatic, but when symptoms occur, the disease has typically reached a clinical stage of focal hemorrhage with irreversible brain damage. We recently reported that the CSC couples both classic (nuclear; nPRs) and nonclassic (membrane; mPRs) progesterone (PRG)-receptors-mediated signaling within the CSC-mPRs-PRG (CmP) signaling network in nPR(−) breast cancer cells. In this report, we demonstrate that depletion of any of the three CCM genes or treatment with mPR-specific PRG actions (PRG/mifepristone) results in the disruption of the CmP signaling network, leading to increased permeability in the nPR(−) endothelial cells (ECs) monolayer in vitro. Finally, utilizing our in vivo hemizygous Ccm mutant mice models, we demonstrate that depletion of any of the three CCM genes, in combination with mPR-specific PRG actions, is also capable of leading to defective homeostasis of PRG in vivo and subsequent BBB disruption, allowing us to identify a specific panel of etiological blood biomarkers associated with BBB disruption. To our knowledge, this is the first report detailing the etiology to predict the occurrence of a disrupted BBB, an indication of early hemorrhagic events.

White matter damage as a consequence of vascular dysfunction in a spontaneous mouse model of chronic mild chronic hypoperfusion with eNOS deficiency

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer’s disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID remain elusive. White matter change represents an invariant feature. Compelling clinical neuroimaging and pathological evidence suggest a link between white matter changes and neurodegeneration. Our prior study detected hypoperfused lesions in mice with partial deficiency of endothelial nitric oxide (eNOS) at very young age, precisely matching to those hypoperfused areas identified in preclinical AD patients. White matter tracts are particularly susceptible to the vascular damage induced by chronic hypoperfusion. Using immunohistochemistry, we detected severe demyelination in the middle-aged eNOS-deficient mice. The demyelinated areas were confined to cortical and subcortical areas including the corpus callosum and hippocampus. The intensity of demyelination correlated with behavioral deficits of gait and associative recognition memory performances. By Evans blue angiography, we detected blood–brain barrier (BBB) leakage as another early pathological change affecting frontal and parietal cortex in eNOS-deficient mice. Sodium nitrate fortified drinking water provided to young and middle-aged eNOS-deficient mice completely prevented non-perfusion, BBB leakage, and white matter pathology, indicating that impaired endothelium-derived NO signaling may have caused these pathological events. Furthermore, genome-wide transcriptomic analysis revealed altered gene clusters most related to mitochondrial respiratory pathways selectively in the white matter of young eNOS-deficient mice. Using eNOS-deficient mice, we identified BBB breakdown and hypoperfusion as the two earliest pathological events, resulting from insufficient vascular NO signaling. We speculate that the compromised BBB and mild chronic hypoperfusion trigger vascular damage, along with oxidative stress and astrogliosis, accounting for the white matter pathological changes in the eNOS-deficient mouse model. We conclude that eNOS-deficient mice represent an ideal spontaneous evolving model for studying the earliest events leading to white matter changes, which will be instrumental to future therapeutic testing of drug candidates and for targeting novel/specific vascular mechanisms contributing to VCID and AD.

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.

Lipids as Early and Minimally Invasive Biomarkers for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Specifically, typical late-onset AD is a sporadic form with a complex etiology that affects over 90% of patients. The current gold standard for AD diagnosis is based on the determination of amyloid status by analyzing cerebrospinal fluid samples or brain positron emission tomography. These procedures can be used widely as they have several disadvantages (expensive, invasive). As an alternative, blood metabolites have recently emerged as promising AD biomarkers. Small molecules that cross the compromised AD blood-brain barrier could be determined in plasma to improve clinical AD diagnosis at early stages through minimally invasive techniques. Specifically, lipids could play an important role in AD since the brain has a high lipid content, and they are present ubiquitously inside amyloid plaques. Therefore, a systematic review was performed with the aim of identifying blood lipid metabolites as potential early AD biomarkers. In conclusion, some lipid families (fatty acids, glycerolipids, glycerophospholipids, sphingolipids, lipid peroxidation compounds) have shown impaired levels at early AD stages. Ceramide levels were significantly higher in AD subjects, and polyunsaturated fatty acids levels were significantly lower in AD. Also, high arachidonic acid levels were found in AD patients in contrast to low sphingomyelin levels. Consequently, these lipid biomarkers could be used for minimally invasive and early AD clinical diagnosis.

EGFR Activation Impairs Antiviral Activity of Interferon Signaling in Brain Microvascular Endothelial Cells During Japanese Encephalitis Virus Infection

The establishment of Japanese encephalitis virus (JEV) infection in brain microvascular endothelial cells (BMECs) is thought to be a critical step to induce viral encephalitis with compromised blood–brain barrier (BBB), and the mechanisms involved in this process are not completely understood. In this study, we found that epidermal growth factor receptor (EGFR) is related to JEV escape from interferon-related host innate immunity based on a STRING analysis of JEV-infected primary human brain microvascular endothelial cells (hBMECs) and mouse brain. At the early phase of the infection processes, JEV induced the phosphorylation of EGFR. In JEV-infected hBMECs, a rapid internalization of EGFR that co-localizes with the endosomal marker EEA1 occurred. Using specific inhibitors to block EGFR, reduced production of viral particles was observed. Similar results were also found in an EGFR-KO hBMEC cell line. Even though the process of viral infection in attachment and entry was not noticeably influenced, the induction of IFNs in EGFR-KO hBMECs was significantly increased, which may account for the decreased viral production. Further investigation demonstrated that EGFR downstream cascade ERK, but not STAT3, was involved in the antiviral effect of IFNs, and a lowered viral yield was observed by utilizing the specific inhibitor of ERK. Taken together, the results revealed that JEV induces EGFR activation, leading to a suppression of interferon signaling and promotion of viral replication, which could provide a potential target for future therapies for the JEV infection.

Association between cerebral blood flow changes and blood–brain barrier compromise in spontaneous intracerebral haemorrhage

To quantitatively evaluate blood-brain barrier (BBB) permeability in the perihaematomal region of spontaneous intracerebral haemorrhage (ICH) and investigate the association between the alterations in cerebral blood flow and BBB permeability around the haematoma. Spontaneous ICH patients underwent unenhanced computed tomography (CT) and CT perfusion (CTP) simultaneously. Haematoma volume was measured on CT. The values of cerebral haemodynamic parameters including cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and permeability-surface area product (PS) were measured in the perihaematomal region and the contralateral mirror region, and then relative values were calculated for statistical analysis. Linear regression was used to evaluate associations between BBB permeability and variables. A total of 87 ICH patients were included in this study. The focally elevated BBB permeability was observed in the perihaematomal region in ICH patients. Linear regression showed that reduced rCBF (β=-0.379, p=0.001) and increased rCBV (β=0.412, p=0.000) correlated independently with increased relative PS (rPS) value in deep ICH, while only increased rCBV (β=0.423, p=0.071) correlated to increased rPS value in patients with lobar ICH. BBB permeability is focally elevated in the region around the haematoma. Cerebral haemodynamic alterations are associated with increased BBB permeability. Cerebral hypoperfusion may aggravate BBB compromise, and a compensatory increase in CBV may lead to reperfusion injury on BBB.

Abstract 387: Blood brain barrier (BBB) disruption by tumor treating fields (TTFields) in a human 3D in vitro model

Abstract The clinical translatability of novel drug delivery systems begins with basic scientific breakthroughs. Our recent discovery of the ability of Tumor Treating Fields (TTFields) to potentially and transiently disrupt the blood brain barrier (BBB) using our murine in vitro and in vivo models, led us to validate our findings in a human 3D in vitro model established in our lab. The model consists of primary brain microvascular endothelial cells co-cultured with immortalized perciytes in a transwell system. TTFields are alternating electric fields of low intensity (1-3V/cm) and intermediate frequency (100-300kHz), which are effective and approved for the treatment of glioblastoma (GBM) using 200kHz frequency. Our murine data point out that TTFields could disrupt the BBB optimally at 100kHz. To investigate if TTFields exhibit similar effects in the human cell-based in vitro model, it was subjected to TTFields at various frequencies for 24-96h. Cells were afterwards made to recover for 24-96h. To assess BBB integrity and compromise, transendothelial electrical resistance (TEER) was measured before start of TTFields, immediately after end of TTFields, as well as 24-96h after TTFields. In addition, a permeability assay was performed. Finally, immunofluorescence (IF) staining visualized the effects of TTFields on tight junction protein claudin-5 localization. TTFields application of all investigated frequencies significantly decreased TEER. However, the strongest effects were observed with 100kHz after 72h. IF staining revealed delocalization of claudin-5 from the cell boundaries to the cytoplasm. Restoration of cell integrity was already evident as early as 24h, with complete recovery after 48h. Results using our human 3D in vitro model validated our previous observations from murine in vitro and in vivo models that TTFields could transiently disrupt the BBB. These findings provide fundamental pre-clinical data for translation from bench to bedside. Accordingly, TTFields demonstrate to be a promising novel approach in opening the BBB to facilitate drug delivery for improved treatment of central nervous system diseases including devastating brain tumors such as GBM. Citation Format: Ellaine Salvador, Almuth F. Kessler, Theresa Köppl, Sebastian Schönhärl, Malgorzata Burek, Catherine Tempel Brami, Tali Voloshin, Moshe Giladi, Ralf-Ingo Ernestus, Mario Löhr, Carola Y. Förster, Carsten Hagemann. Blood brain barrier (BBB) disruption by tumor treating fields (TTFields) in a human 3D in vitro model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 387.

Targeting Oxidative Stress and Inflammatory Response for Blood-Brain Barrier Protection in Intracerebral Hemorrhage.

Significance: Blood-brain barrier (BBB) disruption is a major pathological change after intracerebral hemorrhage (ICH) and is both the cause and result of oxidative stress and of the immune response post-ICH. These processes contribute to ICH-induced brain injury. Recent Advances: After the breakdown of cerebral vessels, blood components, including erythrocytes and their metabolites, thrombin, and fibrinogen, can access the cerebral parenchyma through the compromised BBB, triggering oxidative stress and inflammatory cascades. These aggravate BBB disruption and contribute to further infiltration of blood components, resulting in a vicious cycle that exacerbates brain edema and neurological injury after ICH. Experimental and clinical studies have highlighted the role of BBB disruption in ICH-induced brain injury. Critical Issues: In this review, we focus on the strategies to protect the BBB in ICH. Specifically, we summarize the evidence and the underlying mechanisms, including the ICH-induced process of oxidative stress and inflammatory response, and we highlight the potential therapeutic targets to protect BBB integrity after ICH. Future Directions: Future studies should probe the mechanism of ferroptosis as well as oxidative stress-inflammation coupling in BBB disruption after ICH and investigate the effects of antioxidants and immunomodulatory agents in more ICH clinical trials. Antioxid. Redox Signal. 37, 115-134.

Altered Blood Brain Barrier Permeability and Oxidative Stress in Cntnap2 Knockout Rat Model.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by three core symptoms, specifically impaired social behavior, stereotypic/repetitive behaviors, and sensory/communication deficits. Although the exact pathophysiology of ASD is still unknown, host genetics, oxidative stress, and compromised blood brain barrier (BBB) have been implicated in predisposition to ASD. With regards to genetics, mutations in the genes such as CNTNAP2 have been associated with increased susceptibility of developing ASD. Although some studies observed conflicting results suggesting no association of CNTNAP2 with ASD, other investigations correlated this gene with autism. In addition, CNTNAP2 mediated signaling is generally considered to play a role in neurological disorders due to its critical role in neurodevelopment, neurotransmission, and synaptic plasticity. In this investigation, we studied BBB integrity and oxidative stress in Cntnap2−/− rats. We observed that the BBB permeability was significantly increased in Cntnap2−/− rats compared to littermate wild-type (WT) animals as determined by FITC-dextran and Evans blue assay. High levels of thiobarbituric acid reactive substances and lower amounts of reduced glutathione were observed in brain homogenates of Cntnap2−/− rats, suggesting oxidative stress. Brain sections from Cntnap2−/− rats showed intense inducible nitric oxide synthase immunostaining, which was undetectable in WT animals. Quantification of nitric oxide in brain homogenates revealed significantly high levels in Cntnap2−/− rats compared to the control group. As increased permeability of the BBB and oxidative stress have been observed in ASD individuals, our results suggest that Cntnap2−/− rats have a high construct and face validity and can be explored to develop effective therapeutic modalities.

Targeted Delivery of DNA Topoisomerase Inhibitor SN38 to Intracranial Tumors of Glioblastoma Using Sub-5 Ultrafine Iron Oxide Nanoparticles.

Effectively delivering therapeutics for treating brain tumors is hindered by the physical and biological barriers in the brain. Even with the compromised blood-brain barrier and highly angiogenic blood-tumor barrier seen in glioblastoma (GBM), most drugs, including nanomaterial-based formulations, hardly reach intracranial tumors. This work investigates sub-5nm ultrafine iron oxide nanoparticles (uIONP) with 3.5nm core diameter as a carrier for delivering DNA topoisomerase inhibitor 7-ethyl-10-hydroxyl camptothecin (SN38) to treat GBM. Given a higher surface-to-volume ratio, uIONP shows one- or three-folds higher SN38 loading efficiency (48.3± 6.1%, mg/mg Fe) than those with core sizes of 10 or 20nm. SN38 encapsulated in the coating polymer exhibits pH sensitive release with <10%over 48 h at pH 7.4, but 86% at pH 5, thus being protected from converting to inactive glucuronide by UDP-glucuronosyltransferase 1A1. Conjugating αv β3 -integrin-targeted cyclo(Arg-Gly-Asp-D-Phe-Cys) (RGD) as ligands, RGD-uIONP/SN38 demonstrates targeted cytotoxicity to αv β3 -integrin-overexpressed U87MG GBM cells with a half-maximal inhibitory concentration (IC50 ) of 30.9± 2.2nm. The efficacy study using an orthotopic mouse model of GBM reveals tumor-specific delivery of 11.5% injected RGD-uIONP/SN38 (10mg Fe kg-1 ), significantly prolonging the survival in mice by 41%, comparing to those treated with SN38 alone (p <0.001).

Effects of Nicotine Exposure From Tobacco Products and Electronic Cigarettes on the Pathogenesis of Neurological Diseases: Impact on CNS Drug Delivery

Nicotine, the major component of tobacco smoke (TS) and electronic cigarette (e-cig) vape, has been reported in some cases to be prodromal to cerebrovascular toxicity as well as a promoting factor for the onset of various neurological diseases. In some conditions, pre-exposure to nicotine can lead to a state of compromised blood-brain barrier (BBB) integrity, including altered BBB-related protein expression, BBB leakage, and defective ion and glucose homeostasis within the brain. Moreover, drugs used to treat central nervous system disorders (CNS) have been reported to interact with nicotine and other components of TS/e-cig through both transporter and enzyme-based mechanisms. Herein we discuss nicotine’s potential toxicity at the brain cerebrovasculature and explain how nicotine (from smoking/vaping) may interfere with the uptake of CNS drugs through a CNS drug interaction perspective.

A systematic review of amino acid PET in assessing treatment response to temozolomide in glioma.

The response assessment in neuro-oncology (RANO) criteria have been the gold standard for monitoring treatment response in glioblastoma (GBM) and differentiating tumor progression from pseudoprogression. While the RANO criteria have played a key role in detecting early tumor progression, their ability to identify pseudoprogression is limited by post-treatment damage to the blood-brain barrier (BBB), which often leads to contrast enhancement on MRI and correlates poorly to tumor status. Amino acid positron emission tomography (AA PET) is a rapidly growing imaging modality in neuro-oncology. While contrast-enhanced MRI relies on leaky vascularity or a compromised BBB for delivery of contrast agents, amino acid tracers can cross the BBB, making AA PET particularly well-suited for monitoring treatment response and diagnosing pseudoprogression. The authors performed a systematic review of PubMed, MEDLINE, and Embase through December 2021 with the search terms “temozolomide” OR “Temodar,” “glioma” OR “glioblastoma,” “PET,” and “amino acid.” There were 19 studies meeting inclusion criteria. Thirteen studies utilized [18F]FET, five utilized [11C]MET, and one utilized both. All studies used static AA PET parameters to evaluate TMZ treatment in glioma patients, with nine using dynamic tracer parameters in addition. Throughout these studies, AA PET demonstrated utility in TMZ treatment monitoring and predicting patient survival.

Incidence and Risk Factors for Acute Transient Contrast‐Induced Neurologic Deficit: A Systematic Review With Meta‐Analysis

Background After MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) demonstrated that endovascular therapy improved outcomes in patients with stroke, the number of endovascular procedures has risen sharply. We describe acute transient contrast‐induced neurological deficit (ATCIND), a group of neurological syndromes associated with arterial contrast administration during angiography. Our goal is to elucidate the incidence, risk factors, outcomes, pathogenesis, and diagnostic characteristics of ATCIND. Our primary objective is to elucidate the incidence of ATCIND in the setting of coronary or cerebral angiography. Secondary outcomes include potential risk factors, demographics, treatment modalities, and patient recovery. Methods The data that support the findings of this study are available from the corresponding author on reasonable request. The databases of the Cochrane Library, MEDLINE, Web of Science, and Embase were queried, yielding studies from 1974 to 2021. Inclusion criteria for articles were the following: (1) contrast‐induced encephalopathy, contrast‐induced neurotoxicity, or cortical blindness after contrast administration during angiography were the focus of the article; (2) incidence was reported; (3) studies included ≥3 cases; and (4) follow‐up tests were described to rule out other causes. Exclusion criteria included the following: (1) incidence was not reported; (2) unavailable in the English language; (3) abstracts and unpublished studies; and (4) did not exclude other possible causes, or findings suggested other possible causes, such as worsening ischemic injury. Of 627 articles, 7 were retained. This systematic review with meta‐analysis was performed in accordance with guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) and the Meta‐Analysis of Observational Studies in Epidemiology (MOOSE) checklists. Independent extraction by multiple reviewers was performed. Data were pooled using a random‐effects model. Results The primary study outcome was incidence of ATCIND, which was formulated before data collection began. We hypothesized that the pooled incidence of ATCIND would be similar to that of individual studies. A total of 70 of 21007 patients had the diagnosis of contrast‐induced encephalopathy, contrast‐induced neurotoxicity or angiography‐associated cortical blindness, and ATCIND. The incidence rate of ATCIND is estimated to be 0.51% (CI, 0.3%–1.0%; P &lt;0.001 [ I 2 =29.3]), or 51 per 10 000 patients. Pooled data for risk factors for contrast‐induced encephalopathy were higher contrast dose (odds ratio [OR], 1.072; 95% CI, 0.952–1.192 [ P &lt;0.001]; I 2 =0), and prior stroke (OR, 5.153; CI 1.726–8.581 [ P =0.003]; I 2 =0). Contrast dose &gt;150 mL was a positive, significant predictor of visual disturbance (OR, 7.083; CI, 1.1742–42.793 [ P =0.033]). Full recovery is estimated at 89.5% (95% CI, 76.9%–95.6%; P &lt;0.001 [ I 2 =0]). Conclusions This study confirms the rare incidence of ATCIND, although it shows moderate heterogeneity, likely reflecting the type of angiography performed. Risk factors include larger contrast dose and prior stroke. Full recovery occurs in the majority of patients. It should remain in the differential diagnosis in patients with certain risk factors for blood–brain barrier compromise.

Selective affinity of extravasated brain-reactive IgG autoantibodies for pyramidal neurons is linked to brain amyloid beta deposition, neuronal dysfunction, and cognitive decline.

Amyloid beta plaques (APs) containing amyloid beta peptides (Aβ), blood-brain barrier (BBB) breakdown, and progressive cognitive decline are hallmarks of Alzheimer's disease (AD) pathology. Pathophysiological changes that initiate and perpetuate these hallmarks remain unresolved. We hypothesize that chronic extravasation of immunoglobulin Gs (IgGs) and Aβ via chronically impaired BBB promotes their interaction with pyramidal neurons (PNs). This interaction impairs PN function, consequentially initiates and perpetuates these AD-associated hallmarks. We tested our hypothesis associating neurocognitive decline with BBB breakdown in humans and a mouse model. In humans, antemortem neurocognitive status and postmortem BBB breakdown in their Brodmann area 39/40 were analyzed [AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI) subjects, n=15]. Additionally, we tested the association between chronic BBB compromise, Aβ injection, and long-term memory in CD1 mice (10 months, male, n=33) with Pertussis toxin (PT) injection-induced BBB breach. This mouse-model comprised three injection groups: Saline only, PT+Saline, and PT+Aβ42. We used the immunohistochemistry technique and image-analysis software to track and quantify the fate of blood-borne Aβ42 in mouse brain by injecting synthetic, fluorescent-tagged monomeric Aβ42 (F-Aβ42). We used Lashley's III Maze and Water Maze to evaluate the impact of BBB breach and Aβ42 injection on animals' long-term memory. Brodmann areas 39/40 of AD subjects showed a greater incidence and extent of BBB breach than MCI and NCI subjects. Cognitive test results demonstrating reduced cognitive function for Brodmann areas 39/40 correlated with the extent of BBB breach. Likewise, PT+Aβ42 mice exhibited increased BBB permeability and selectively heightened immunoreactivity between PNs and extravasated IgGs compared to other groups. Since these IgGs target "self" epitopes in the brain parenchyma, we refer to this subset of IgGs as brain-reactive autoantibodies (BrAbs). Additionally, in PT+Aβ42 mice, we observed intraneuronal accumulations of F-Aβ42 in cortical and hippocampal PNs and significant impairment in long-term memory. In AD pathogenesis, BBB compromise induces chronic extravasation of BrAbs and Aβ, an event that serves as a mechanistic link that initiates and perpetuates Aβ deposition in PNs. Deposition of Aβ may perturb PN function and lead to progressive cognitive decline.

Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients.

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood–brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood–brain barrier.

Acute Mountain Sickness Following Incremental Trekking to High Altitude: Correlation With Plasma Vascular Endothelial Growth Factor Levels and the Possible Effects of Dexamethasone and Acclimatization Following Re-exposure.

Purpose: The recognition and treatment of high-altitude illness (HAI) is increasingly important in global emergency medicine. High altitude related hypobaric hypoxia can lead to acute mountain sickness (AMS), which may relate to increased expression of vascular endothelial growth factor (VEGF), and subsequent blood-brain barrier (BBB) compromise. This study aimed to establish the relationship between AMS and changes in plasma VEGF levels during a high-altitude ascent. VEGF level changes with dexamethasone, a commonly used AMS medication, may provide additional insight into AMS.Methods: Twelve healthy volunteers ascended Mt Fuji (3,700 m) and blood samples were obtained at distinct altitudes for VEGF analysis. Oxygen saturation (SPO2) measurements were also documented at the same time-point. Six out of the 12 study participants were prescribed dexamethasone for a second ascent performed 48 h later, and blood was again collected to establish VEGF levels.Results: Four key VEGF observations could be made based on the data collected: (i) the baseline VEGF levels between the two ascents trended upwards; (ii) those deemed to have AMS in the first ascent had increased VEGF levels (23.8–30.3 pg/ml), which decreased otherwise (23.8–30.3 pg/ml); (iii) first ascent AMS participants had higher VEGF level variability for the second ascent, and similar to those not treated with dexamethasone; and (iv) for the second ascent dexamethasone participants had similar VEGF levels to non-AMS first ascent participants, and the variability was lower than for first ascent AMS and non-dexamethasone participants. SPO2 changes were unremarkable, other than reducing by around 5% irrespective of whether measurement was taken for the first or second ascent.Conclusion: First ascent findings suggest a hallmark of AMS could be elevated VEGF levels. The lack of an exercise-induced VEGF level change strengthened the notion that elevated plasma VEGF was brain-derived, and related to AMS.

Investigation of Neurodevelopmental Deficits of 22 q11.2 Deletion Syndrome with a Patient-iPSC-Derived Blood-Brain Barrier Model.

The blood–brain barrier (BBB) is important in the normal functioning of the central nervous system. An altered BBB has been described in various neuropsychiatric disorders, including schizophrenia. However, the cellular and molecular mechanisms of such alterations remain unclear. Here, we investigate if BBB integrity is compromised in 22q11.2 deletion syndrome (also called DiGeorge syndrome), which is one of the validated genetic risk factors for schizophrenia. We utilized a set of human brain microvascular endothelial cells (HBMECs) derived from the induced pluripotent stem cell (iPSC) lines of patients with 22q11.2-deletion-syndrome-associated schizophrenia. We found that the solute permeability of the BBB formed from patient HBMECs increases by ~1.3–1.4-fold, while the trans-endothelial electrical resistance decreases to ~62% of the control values. Correspondingly, tight junction proteins and the endothelial glycocalyx that determine the integrity of the BBB are significantly disrupted. A transcriptome study also suggests that the transcriptional network related to the cell–cell junctions in the compromised BBB is substantially altered. An enrichment analysis further suggests that the genes within the altered gene expression network also contribute to neurodevelopmental disorders. Our findings suggest that neurovascular coupling can be targeted in developing novel therapeutical strategies for the treatment of 22q11.2 deletion syndrome.

Mesenchymal Stem/Stromal Cell Therapy in Blood-Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects.

Ischemic stroke is the leading cause of mortality and long-term disability worldwide. Disruption of the blood–brain barrier (BBB) is a prominent pathophysiological mechanism, responsible for a series of subsequent inflammatory cascades that exacerbate the damage to brain tissue. However, the benefit of recanalization is limited in most patients because of the narrow therapeutic time window. Recently, mesenchymal stem cells (MSCs) have been assessed as excellent candidates for cell-based therapy in cerebral ischemia, including neuroinflammatory alleviation, angiogenesis and neurogenesis promotion through their paracrine actions. In addition, accumulating evidence on how MSC therapy preserves BBB integrity after stroke may open up novel therapeutic targets for treating cerebrovascular diseases. In this review, we focus on the molecular mechanisms of MSC-based therapy in the ischemia-induced prevention of BBB compromise. Currently, therapeutic effects of MSCs for stroke are primarily based on the fundamental pathogenesis of BBB breakdown, such as attenuating leukocyte infiltration, matrix metalloproteinase (MMP) regulation, antioxidant, anti-inflammation, stabilizing morphology and crosstalk between cellular components of the BBB. We also discuss prospective studies to improve the effectiveness of MSC therapy through enhanced migration into defined brain regions of stem cells. Targeted therapy is a promising new direction and is being prioritized for extensive research.