Intra-cerebrospinal fluid (CSF) drug delivery bypasses the blood-brain barrier, making it a promising route of delivery to treat central nervous system (CNS) diseases. Optimizing this delivery route is challenging because of complex interactions among drug kinetics, CSF flow dynamics and anatomical variations. Non-human primate (NHP) models provide an approximation to human physiology, making a suitable surrogate for studying intra-CSF drug dispersion. We present a NHP digital model for pharmacokinetic prediction of intra-CSF solute neuraxial dispersion that incorporates craniospinal compliance and other key physiological features.

Ventricular collapse is a prevalent yet poorly understood complication of ventriculo-peritoneal shunting (VPS) in idiopathic intracranial hypertension (IIH). By identifying the risk factors of ventricular collapse (VC), this study aims to characterize the clinical progression and treatment of IIH and its complications. The relationships between ventricular area, symptoms and treatments were assessed longitudinally with ventricular segmentation on MRI/CT imaging, and correlated with other risk factors of IIH and VC.

Choroid plexus (ChP) is responsible for producing cerebrospinal fluid, which is increasingly recognized as important in the context of aging and Alzheimer’ disease (AD). However, structural alteration (especially cystic alteration) of ChP across the pathologically confirmed AD continuum remains unclear.

Multiple sclerosis (MS) is a chronic inflammatory disease that has been associated with dysfunction of the protective barriers in the central nervous system (CNS), allowing harmful immune cells to enter. Growing evidence implicates gut microbiota dysbiosis in MS pathogenesis, yet its connection to CNS barrier integrity is not fully understood. To address this, we investigated the role of gut microbiota in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by depleting intestinal microbes using a broad-spectrum antibiotic (ABX) regimen. Our results indicate that ABX-mediated gut microbiota depletion was associated with a milder EAE disease course, accompanied by reduced immune cell infiltration and attenuation of EAE-associated loss of barrier integrity. These improvements coincided with preserved expression and localization of tight junction (TJ) proteins, vital for maintaining barrier integrity. While these data support a microbiota-mediated effect, ABX compounds may also exert microbiota-independent immunomodulatory actions. Importantly, although ABX treatment proved beneficial in the inflammatory EAE setting, antibiotics are also known to disrupt immune and barrier homeostasis under steady-state conditions, highlighting their dual and context-dependent nature. To further look into this, we transferred gut microbiota between EAE and healthy mice and observed a microbiota-dependent effect on CNS barrier integrity. Next, treatment with SCFAs partly restored the disrupted CNS barriers and was linked to reduced disease development in EAE. Altogether, our findings suggest that the gut microbiota has dual role in the CNS barriers in MS. These findings align with emerging literature identifying gut-derived signals, particularly under antibiotic perturbation or through microbial metabolites, as critical modulators of neuroimmune homeostasis. Additionally, our results highlight the potential of microbiota-targeted interventions and SCFAs to influence CNS barrier integrity and disease outcomes.

The ependymal glycocalyx (Gcx) is a glycan-rich apical structure that lines the ventricular brain surface. It is thought to contribute to cerebrospinal fluid dynamics and brain homeostasis by forming a selective barrier, preserving surface charge, and supporting ciliary function. Despite its importance, the structural integrity and glycan composition of the ependymal Gcx remain poorly understood, particularly in the context of physiological aging and acute neurological injury, such as intraventricular hemorrhage (IVH). We aimed to elucidate the physiological role of the ependymal Gcx and its alterations in response to aging and acute brain injury.

To quantify the pericyte density in the macular capillaries, define the distribution of the transition zones, and characterize inter-pericyte tunneling nanotubules (IP-TNTs) in postmortem donor eyes.

The choroid plexus-cerebrospinal fluid (ChP-CSF) interface regulates a microenvironment supporting neural stem cell growth, strongly affected by hypoxia through ChP function. From human induced pluripotent stem cells (hiPSCs), here we established and validated in vitro ChP organoid secreting CSF-like fluid (iCSF) and exposed them to low oxygen atmosphere for 24 h. Transcriptomic indicated major data on morphological and functional alterations in the ChP cells and shotgun proteomics revealed significant changes in proteins involved in energy metabolism and mitochondrial function. We found that H2AZ and ITM2B, involved in neurogenesis and neurite growth, were the key proteins downregulated in hypoxic iCSF and ChP organoids, respectively. Positive correlation analysis between hypoxia-induced mRNA expression of the neuronal progenitor biomarkers SOX2 and PAX6. Mature neuron MAP2 and H2AZ also confirmed impairment of neurogenesis. The results from this study suggest that ChP-CSF interface opens new opportunities to characterize hypoxic brain pathophysiology and discover novel biomarkers.

Brain endothelial cells (ECs) lining blood vessels are essential for the normal function of the brain. They form the first layer of the blood-brain barrier (BBB) and regulate nutrient exchange, immune responses, and angiogenesis. Numerous studies have reported the disruption of the BBB in neurodegenerative diseases, including Alzheimer’s disease (AD). However, the impact of cell-intrinsic amyloid pathology on EC function remains to be clarified.

The development of brain-targeted delivery systems is significantly hindered by the blood-brain barrier (BBB), which prevents drugs from effectively reaching therapeutic regions in the brain. To evaluate drug efficacy and study pathogenesis, BBB models are used to simulate the brain microenvironment and the action of the BBB. In vitro models, which overcome the cost and ethical issues associated with animal models and avoid species-specific differences, are particularly valuable. However, traditional in vitro models, such as two-dimensional cell cultures and transwell systems, lack three-dimensional structure and physiological and mechanical conditions, including shear stress, making it challenging for endothelial cells (ECs) to recapitulate BBB properties. Recent advancements have incorporated microfluidics and gel materials to support cell growth into BBB models, enabling near physiological replication of the BBB in vitro to mimic pathogenesis and critical physiological and pathological processes. This paper discusses recent advancements in in vitro BBB modeling, current design concepts for microfluidic BBB models, and key influencing factors. It also reviews different types of hydrogels used in microfluidic platforms for the BBB, highlighting their respective features. Furthermore, it explores potential biocompatible hydrogel structures for future applications in microfluidic BBB models, aiming to provide valuable data and a theoretical foundation for future BBB model optimization.

Transferrin receptor-1 (TfR1) transcytosis-mediated delivery of therapeutic monoclonal antibodies across the blood-brain barrier (BBB) is a promising concept in drug development for CNS disorders. In this study, we investigated brain delivery and effects on plaque burden of Aducanumab (Adu), a clinically validated anti-amyloid beta (Aβ) antibody, when fused to a mouse TfR1-binding Fab fragment as BBB shuttle (TfR1-Adu).

Research on the blood-brain barrier (BBB) has greatly evolved over the past 20 years, with growing recognition of its role as a multicellular complex regulating brain homeostasis. Previously confined to pharmaceutical sciences, the BBB has now become a growing focus of interest for neuroscientists and clinicians. However, the word ‘barrier’, implying something that can be broken, opened, or disrupted, can lead to confusion when one tries to relate this concept to its underlying cell biology. Here, echoing the fundamental question posed by Lina Stern when she first defined the BBB in 1921, I suggest that the confusion stems from conflating the physicochemical properties intrinsic to the barrier with the living biological multicellular interface. Notwithstanding its complexity, the BBB is now often simplistically portrayed as “permeable”, particularly in the context of prevalent diseases, such as Alzheimer’s, depression, multiple sclerosis, or stroke. Such overly simplified concepts promoted over the past two decades have led to misconceptions that hinder a proper understanding of the BBB, affecting both the general public and seasoned scientists. This misunderstanding is not without harmful clinical impact as many interpret the BBB as something that often breaks, leading to a massive entry of drugs and other blood-borne compounds into the brain, which is very rarely the case. After outlining the likely causes of these misconceptions and trying to define the concepts of “BBB permeability” and “brain bioavailability”, I offer several recommendations: (1) more frequent use of quantitative methods involving small hydrophilic compounds to measure BBB integrity; (2) avoid terms such as ‘BBB disruption,’ ‘opening,’ or ‘breakdown,’ and instead favor terms like ‘dysfunction’ or, where appropriate, ‘leakage’, essentially when describing biological defects assessed by changes in large molecule localization; and (3) always account for the dual nature of the BBB, as both a physicochemical barrier and a living biological interface.

According to our previous findings, the integrity of the blood-brain barrier (BBB) is affected by tobacco smoke (TSe) and electronic cigarette (ECe) exposure, and metformin (MF) can counter these detrimental effects. It is unknown, therefore, if MF protects against neuronal dysfunction after BBB damage caused by either TSe or ECe alone or combined exposure (TSe and ECe) in stroke cases. Additionally, MF's ability to enter the ischemic brain during ischemic stroke is unknown. The purpose of this effort is to address these questions.

High-Density Lipoprotein (HDL) not only mediates reverse cholesterol transport in the periphery but also significantly influences Blood-Brain Barrier (BBB) function within the central nervous system by regulating lipid metabolism, inflammatory responses, oxidative stress, Aβ trans-barrier clearance, and endothelial nitric oxide signaling. Variations in structural composition and biological properties between plasma HDL and brain-derived HDL-like particles enable them to perform both synergistic and distinct roles in maintaining cholesterol homeostasis, protecting tight junctions, regulating barrier permeability, facilitating Aβ efflux, and stabilizing the neurovascular unit. Key components such as ApoA-I, the ApoM/Sphingosine-1-Phosphate (S1P) signaling axis, and ApoE preserve BBB integrity by enhancing endothelial and pericyte functions, stabilizing intercellular junctions, inhibiting matrix metalloproteinase activity, and reducing neuroinflammation. Additionally, HDL/HDL-like particles alleviate barrier stress by facilitating the clearance of metabolic waste through the glymphatic system. Existing research collectively suggests that HDL-like particles, as a multifaceted regulator of BBB homeostasis, play a crucial role in maintaining neurological health and influencing disease processes.

A recent paper suggests that the water originating from the ATP production coupled to aerobic glucose oxidation causes more than a 6 fold increase in the production of metabolic water, compared with the standard textbook description of the oxidation process. However, the authors seem to have forgotten that the simultaneous processes of ATP utilization takes up the same amount of water, which was liberated during the ATP synthesis. Thus, at steady state, there is no net increase in the production of metabolic water.

The brain-meninges interface, comprising of astrocytes and meningeal cells seperated by a shared basement membrane, plays critical roles in the central nervous system. Recent work has shown the importance of signalling between the brain and the meninges in neurodevelopment, health, disease, and in stem cell migration. Despite this recent research, the brain-meninges interface is significantly understudied. This systematic review evaluates 27 studies which examine astrocyte-meningeal cell co-culture models. The papers were identified from a search of PubMed, Scopus, and Web of Science and screened for eligibility according to the PRISMA guidelines. These papers utilized the astrocyte-meningeal cell co-culture to mimic different biological interfaces within the central nervous system such as the spinal cord, optic nerve, and the brain-meninges interface to examine various outcomes such as neurite outgrowth, morphology, glial scar formation, and protein expression. Our findings highlight significant gaps in our understanding of the brain-meninges interface, along with inconsistencies in methodologies when establishing the astrocyte-meningeal cell co-culture model. Finally, this review recommends a standardisation of methodologies for astrocyte-meningeal cell co-culture including model validation and detailed protocols. This will allow for improved understanding of these important interfaces in the brain.

A Comment to our recent paper that described a budget for brain metabolic water production claimed that all ATP produced by oxidation of glucose is consumed by hydrolysis, and that the net calculated production of metabolic water is equal to that obtained by combustion of glucose. However, ATP is synthesized and consumed by enzymatic reactions that do not involve water in the mechanism. Not all ATP consumed is hydrolyzed.

The white matter damage inducing the reemergence of grasp reflexes and their potential lateralization remains unstudied. Idiopathic normal pressure hydrocephalus (iNPH), a subcortical dementia, is an ideal model for these investigations. We aim to understand the contributions of white matter to the inhibition of grasp reflexes in patients with iNPH.

Neurofluid flow dynamics are frequently studied from asynchronous blood and CSF flow measurements from real-time imaging using separate phase contrast (PC) MRI scans. Asynchronous measures can be influenced by changes in heart rate, respiration, and other physiological processes, obfuscating neurofluids assessment. Here we present an approach for synchronous measures of neurofluids using simultaneous real-time 2D PC MRI and investigated the effects of different breathing patterns on synchronous and asynchronous blood and CSF flow in a group of healthy participants.

Cerebral small vessel disease (CSVD) encompasses diffuse brain lesions arising from structural injury to small vessels, and is closely associated with chronic hypoperfusion and blood-brain barrier (BBB) dysfunction. Its insidious onset and heterogeneous clinical manifestations render elucidation of its pathogenesis and development of targeted interventions of paramount clinical importance. Transforming growth factorβ (TGFβ), a pivotal regulator of vascular homeostasis, exerts bidirectional effects within the neurovascular unit (NVU) during CSVD: under physiological conditions, TGFβ maintains barrier integrity by modulating endothelial tight junction proteins and pericyte adhesion; under pathological stress, dysregulated TGFβ signaling induces endothelial dysfunction, pericyte degeneration and neuroinflammation, thereby promoting white-matter injury. Precise, spatiotemporal modulation of TGFβ pathways therefore represents a promising avenue for stage-specific, molecularly targeted therapy in CSVD.

In vitro evaluation of substances utilizing the putative proton‑coupled organic cation (H/OC) antiporter for active uptake across the blood-brain barrier (BBB) and brain cell membranes requires a thorough understanding of cellular pharmacokinetics supported by reliable translational readouts. This study assessed the rate and extent of uptake of the antiporter substrate oxycodone in brain endothelial and parenchymal cells at clinically relevant concentrations, exploring the suitability of various cell models for investigating active drug transport.