Microvascular disease of the brain

Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) are a critical but frequently underestimated aspect of cerebral small vessel disease (CSVD), bearing substantial clinical consequences. Detectable through sensitive neuroimaging techniques, CMHs reveal an extensive pathological landscape. They are prevalent in the aging population, with multiple CMHs often being observed in a given individual. CMHs are closely associated with accelerated cognitive decline and are increasingly recognized as key contributors to the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD)...

SARS-CoV-2-induced excessive inflammation in brain leads to damage of blood-brain barrier, hypoxic-ischemic injury, and neuron degeneration. The production of inflammatory cytokines by brain microvascular endothelial cells and microglia is reported to be critically associated with the brain pathology of COVID-19 patients. However, the cellular mechanisms for SARS-CoV-2-inducing activation of brain cells and the subsequent neuroinflammation remain to be fully delineated. Our research, along with others', has recently demonstrated that SARS-CoV-2-induced accumulation and activation of mast cells (MCs) in mouse lung could further induce inflammatory cytokines and consequent lung damages...

At present, there is limited research on the mechanisms underlying moyamoya disease (MMD). Herein, we aimed to determine the role of glutamine in MMD pathogenesis, and 360 adult patients were prospectively enrolled. Human brain microvascular endothelial cells (HBMECs) were subjected to Integrin Subunit Beta 4 (ITGB4) overexpression or knockdown and atorvastatin. We assessed factors associated with various signaling pathways in the context of the endothelial-to-mesenchymal transition (EndMT), and the expression level of related proteins was validated in the superficial temporal arteries of patients...

BACKGROUND: Vasodilation, autoregulation, and rising arterial pressure are three common concepts in cerebral compression, believed to improve cerebral blood flow to maintain the brain's nutrition. However, these concepts are unclear, unproven, and based on assumptions. This study aimed to correlate cerebral circulation with alterations of vital signs and to evaluate the above concepts based on physics and hemodynamics. METHODS: Without new animal experiments, a large amount of data: recording of vital signs, long movies of cerebral circulation, and numerous photos of histological examination and microvessels obstruction in cerebral compression in cats was studied, and only partial and preliminary results were reported in 1970...

Infection with Plasmodium falciparum is often deadly when it results in cerebral malaria, which is associated with neuropathology described as an overwhelming inflammatory response and mechanical obstruction of cerebral microvascular. PI3Kγ is a critical component of intracellular signal transduction and plays a central role in regulating cell chemotaxis, migration, and activation. The purpose of this study was to examine the relationship between inhibiting the PI3Kγ pathway and the outcome of experimental cerebral malaria (ECM) in C57BL/6J mice infected with the mouse malaria parasite, Plasmodium berghei ANKA...

This review article focuses on the upstream pertinent pathophysiology leading to neurodegenerative disease. Specifically, the nexus appears to be blood-brain barrier (BBB) leakiness resulting in a two-prong inflammatory disease spectrum damaging the microvasculature and corrupting protein synthesis and degradation with accumulating misfolded toxic proteins. The suboptimal results of removing misfolded proteins mean a new approach to disease in the preclinical state is required aimed at other targets. Validated noninvasive imaging and serologic biomarkers of early preclinical disease implemented in the high-risk patient cohort along with periodic surveillance once effective treatments are developed will be required...

BACKGROUND: Moyamoya disease (MMD) is characterized by an abundance of moyamoya vessels; however, the precise mechanism driving the spontaneous angiogenesis of these compensatory vessels remains unclear. Previous research has established a link between the stromal cell-derived factor-1 (SDF-1)/ CXC receptor 4 (CXCR4) axis and angiogenesis under hypoxic conditions. Nevertheless, the alterations in this axis within the cerebrospinal fluid, arachnoid membranes and vascular tissue of MMD patients have not been fully investigated...

The blood-brain barrier (BBB) serves as a highly intricate and dynamic interface connecting the brain and the bloodstream, playing a vital role in maintaining brain homeostasis. BBB dysfunction has been associated with multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS); however, the role of the BBB in neurodegeneration is understudied. We developed an ALS patient-derived model of the BBB by using cells derived from 5 patient donors carrying C9ORF72 mutations. Brain microvascular endothelial-like cells (BMEC-like cells) derived from C9ORF72-ALS patients showed altered gene expression, compromised barrier integrity, and increased P-glycoprotein transporter activity...

A series of tacrine-donepezil hybrids were synthesized as potential multifunctional anti-Alzheimer's disease (AD) compounds. For this purpose, tacrine and the benzylpiperidine moiety of donepezil were fused with a hydrazone group to achieve a small library of tacrine-donepezil hybrids. In agreement with the design, all compounds showed inhibitory activity toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values in the low micromolar range. Kinetic studies on the most potent cholinesterase (ChE) inhibitors within the series showed a mixed-type inhibition mechanism on both enzymes...

Flaviviruses in the Japanese encephalitis virus (JEV) serogroup, such as JEV, West Nile virus, and St. Louis encephalitis virus, can cause severe neurological diseases. The nonstructural protein 1 (NS1) is a multifunctional protein of flavivirus that can be secreted by infected cells and circulate in the host bloodstream. NS1' is an additional form of NS1 protein with 52 amino acids extension at its carboxy-terminal and is produced exclusively by flaviviruses in the JEV serogroup. In this study, we demonstrated that the secreted form of both NS1 and NS1' can disrupt the blood-brain barrier (BBB) of mice, with NS1' exhibiting a stronger effect...

PURPOSE: Intravoxel incoherent motion (IVIM) is a quantitative magnetic resonance imaging (MRI) method used to quantify perfusion properties of tissue non-invasively without contrast. However, clinical applications are limited by unreliable parameter estimates, particularly for the perfusion fraction (f) and pseudodiffusion coefficient (D*). This study aims to develop a high-fidelity reconstruction for reliable estimation of IVIM parameters. The proposed method is versatile and amenable to various acquisition schemes and fitting methods...

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which is associated with various neurological symptoms, including nausea, dizziness, headache, encephalitis, and epileptic seizures. SARS-CoV-2 is considered to affect the central nervous system (CNS) by interacting with the blood-brain barrier (BBB), which is defined by tight junctions that seal paracellular gaps between brain microvascular endothelial cells (BMECs). Although SARS-CoV-2 infection of BMECs has been reported, the detailed mechanism has not been fully elucidated...

Zoonotic streptococci cause several invasive diseases with high mortality rates, especially meningitis. Numerous studies elucidated the meningitis pathogenesis of zoonotic streptococci, some specific to certain bacterial species. In contrast, others are shared among different bacterial species, involving colonization and invasion of mucosal barriers, survival in the bloodstream, breaching the blood-brain and/or blood-cerebrospinal fluid barrier to access the central nervous system, and triggering inflammation of the meninges...

BACKGROUND: Acute neurological manifestation is a common complication of acute Coronavirus Disease 2019 (COVID-19) disease. This retrospective cohort study investigated the 3-year outcomes of patients with and without significant neurological manifestations during initial COVID-19 hospitalization. METHODS AND FINDINGS: Patients hospitalized for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection between 03/01/2020 and 4/16/2020 in the Montefiore Health System in the Bronx, an epicenter of the early pandemic, were included...

In multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), early pathological features include immune cell infiltration into the central nervous system (CNS) and blood-brain barrier (BBB) disruption. We investigated the role of junctional adhesion molecule-A (JAM-A), a tight junction protein, in active EAE (aEAE) pathogenesis. Our study confirms JAM-A expression at the blood-brain barrier and its luminal redistribution during aEAE. JAM-A deficient (JAM-A-/- ) C57BL/6J mice exhibited milder aEAE, unrelated to myelin oligodendrocyte glycoprotein-specific CD4+ T-cell priming...

In the brain, environmental changes, such as neuroinflammation, can induce senescence, characterized by the decreased proliferation of neurons and dendrites and synaptic and vascular damage, resulting in cognitive decline. Senescence promotes neuroinflammatory disorders by senescence-associated secretory phenotypes and ROS. In human brain microvascular endothelial cells (HBMVECs), we demonstrate that chronological aging and irradiation increase death-associated protein kinase 3 (DAPK3) expression. To confirm the role of DAPK3 in HBMVEC senescence, we disrupted DAPK3 activity using small interfering RNA (siRNA) or a dominant-negative mutant (DAPK3-P216S), which reduced cellular senescence phenotypes, as assessed by changes in tube formation, senescence-associated beta-galactosidase activity, and cell proliferation...

Over the past decades, evidence has consistently shown that treatment of central nervous system (CNS)-related disorders, including Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis, and brain cancer, is limited due to the presence of the blood-brain barrier (BBB). To assist with the development of new therapeutics, it is crucial to engineer a drug delivery system that can cross the BBB efficiently and reach target cells within the brain. In this study, we present a potentially efficient strategy for targeted brain delivery through utilization of folic acid (FA)-conjugated brush polymers, that specifically target the reduced folate carrier (RFC, SLC19A1) expressed on brain endothelial cells...

Advances in monitoring and treatment of people living with Type 1 Diabetes (T1D) have led to longer life expectancy, but with it an ageing population of T1D patients with age-associated conditions. While diabetic macrovascular, brain, eye, nerve and kidney complications are widely recognized, bone fragility with concomitant fracture has received considerably less attention, even though bone fractures lead to very high morbidity and mortality. Hip fracture risk is up to 6-fold higher in T1D compared to age- and sex-matched non-diabetic controls and is significantly higher than in type 2 diabetes...

Mouse models are invaluable to understanding fundamental mechanisms in vascular biology during development, in health and different disease states. Several constitutive or inducible models that selectively knockout or knock in genes in vascular endothelial cells exist; however, functional and phenotypic differences exist between microvascular and macrovascular endothelial cells in different organs. In order to study microvascular endothelial cell-specific biological processes, we developed a Tamoxifen-inducible von Willebrand Factor (vWF) Cre recombinase mouse in the SJL background...

Bacterial meningitis is a severe and life-threatening disease that rapidly progresses in neonates and infants; prompt diagnosis and appropriate treatment are lifesaving. Magnetic resonance imaging remains the primary imaging technique for diagnosing meningitis; however, due to its limited availability and cost, ultrasound is often used for initial screening. Microvascular imaging ultrasound (MVI) is an emerging technique that offers insight into the brain microvasculature beyond conventional ultrasound. Here we present three patients with confirmed bacterial meningitis and associated cerebral microvascular findings on brain MVI to instigate further validation of cerebral microvascular imaging markers of bacterial meningitis for early detection and intervention...