FLUIDS AND BARRIERS OF THE CNS 是一本开放获取、同行评审的期刊，考虑所有 CNS 液体和屏障系统在健康和疾病中的手稿。通过脑液和屏障的正常功能维持神经系统内部环境的稳态至关重要为了机体的健康。脑脊液 (CSF) 及其组成、循环和吸收在正常和异常的脑功能中具有多种作用，并且与脑实质间质液和血脑屏障处的神经血管单元密切相关。包括血脑脊液屏障、血脑屏障、血视网膜屏障和血神经屏障在内的中枢神经系统流体和屏障系统执行流体分泌、化学信号传导、物理和化学缓冲、专门的定向运输和促进免疫监视。

Fluids and Barriers of the CNS is an open-access, peer-reviewed journal that focuses on the study of central nervous system (CNS) fluids and barrier systems in health and disease. Cerebrospinal fluid (CSF) and its components, circulation, and absorption play critical roles in normal and abnormal brain function, closely interacting with the neurovascular unit at the brain parenchyma interstitial fluid and the blood-brain barrier. The fluid and barrier systems of the central nervous system, including the blood-cerebrospinal fluid barrier, blood-brain barrier, blood-retinal barrier, and blood-nerve barrier, are responsible for fluid secretion, chemical signaling, physical and chemical buffering, specialized directional transport, and facilitating immune surveillance, all of which are essential for maintaining the homeostasis of the internal environment of the nervous system.

《Fluids and Barriers of the CNS》是一本开放获取、同行评审的期刊，专注于中枢神经系统（CNS）液体和屏障系统在健康与疾病中的研究。脑脊液（CSF）及其成分、循环和吸收在正常和异常脑功能中发挥着重要作用，并与脑实质间质液和血脑屏障的神经血管单元密切相关。中枢神经系统的液体和屏障系统，包括血脑脊液屏障、血脑屏障、血视网膜屏障和血神经屏障，负责流体分泌、化学信号传导、物理和化学缓冲、特定的定向运输以及促进免疫监视，这些功能对于维持神经系统内部环境的稳态至关重要。

Fluids and Barriers of the CNS

Nanotubular structures, denoted tunneling nanotubes (TNTs) have been described in recent times as involved in cell-to-cell communication between distant cells. Nevertheless, TNT-like, long filopodial processes had already been described in the last century as connecting facing, growing microvessels during the process of cerebral cortex vascularization and collateralization. Here we have investigated the possible presence and the cellular origin of TNTs during normal brain vascularization and also in highly vascularized brain tumors.We searched for TNTs by high-resolution immunofluorescence confocal microscopy, applied to the analysis of 20-µm, thick sections from lightly fixed, unembedded samples of both developing cerebral cortex and human glioblastoma (GB), immunolabeled for endothelial, pericyte, and astrocyte markers, and vessel basal lamina molecules.The results revealed the existence of pericyte-derived TNTs, labeled by proteoglycan NG2/CSPG4 and CD146. In agreement with the described heterogeneity of these nanostructures, ultra-long (> 300 µm) and very thin (< 0.8 µm) TNTs were observed to bridge the gap between the wall of distant vessels, or were detected as short (< 300 µm) bridging cables connecting a vessel sprout with its facing vessel or two apposed vessel sprouts. The pericyte origin of TNTs ex vivo in fetal cortex and GB was confirmed by in vitro analysis of brain pericytes, which were able to form and remained connected by typical TNT structures.None of the multiple roles described for TNTs can be excluded from a possible involvement during the processes of both normal and pathological vessel growth. A possible function, suggested by the pioneering studies made during cerebral cortex vascularization, is in cell searching and cell-to-cell recognition during the processes of vessel collateralization and vascular network formation. According to our results, it is definitely the pericyte-derived TNTs that seem to actively explore the surrounding microenvironment, searching for (site-to-site recognition), and connecting with (pericyte-to-pericyte and/or pericyte-to-endothelial cell communication), the targeted vessels. This idea implies that TNTs may have a primary role in the very early phases of both physiological and tumor angiogenesis in the brain.

Mariella Errede

Domenica Mangieri

Giovanna Longo

Francesco Girolamo

Ignazio de Trizio

Antonella Vimercati

Gabriella Serio

Karl Frei

Roberto Perris

Daniela Virgintino

Tunneling nanotubes evoke pericyte/endothelial communication during normal and tumoral angiogenesis

在正常和肿瘤血管生成过程中， tunneling nanotubes 引发周细胞/内皮细胞通讯

Our previous study demonstrated that M1 macrophages could impair tight junctions (TJs) between vascular endothelial cells by secreting interleukin-6 (IL-6) after spinal cord injury (SCI). Tocilizumab, as a humanized IL-6 receptor (IL-6R) monoclonal antibody approved for the clinic, has been applied in the treatment of neurological diseases in recent years, but the treatment effect of Tocilizumab on the TJs restoration of the blood-spinal cord barrier (BSCB) after SCI remains unclear. This study aimed to explore the effect of Tocilizumab on the restoration of TJs between vascular endothelial cells and axon regeneration after SCI.
In this study, the mouse complete spinal cord crush injury model was used, and Tocilizumab was continuously injected intrathecally until the day of sample collection. A PBS injection in the same location was included as a control. At 14 days postinjury (dpi) and 28 dpi, spinal cord tissue sections were examined via tissue immunofluorescence. The Basso Mouse Scale (BMS) scores and footprint analysis were used to verify the effect of Tocilizumab on the recovery of motor function in mice after SCI.
We demonstrated that depletion of macrophages has no effect on axon regeneration and motor functional recovery after SCI, but mice subjected to Tocilizumab showed a significant increase in axon regeneration and a better recovery in motor function during the chronic phase after SCI. Moreover, our study demonstrated that at 14 and 28 dpi, the expression of claudin-5 (CLDN5) and zonula occludens-1 (ZO-1) between vascular endothelial cells was significantly increased and the leakage of BSCB was significantly reduced in the injured core after daily intrathecal injection of Tocilizumab. Notably, the infiltration of CD68+macrophages/microglia and the formation of fibrotic scar were decreased in the injured core after Tocilizumab treatment. Tocilizumab treatment could effectively reduce the IL-6 expression in macrophages in the injured core.
The application of Tocilizumab to antagonize IL-6R can effectively reduce the expression of IL-6 in macrophages and facilitate TJs restoration of the BSCB, which is beneficial for axon regeneration and motor functional recovery after SCI. Hence, Tocilizumab treatment is a potential therapeutic strategy for SCI.

Yang Luo

Fei Yao

Yi Shi

Zhenyu Zhu

Zhaoming Xiao

Xingyu You

Yanchang Liu

Shuisheng Yu

Dasheng Tian

Li Cheng

Meige Zheng

Juehua Jing

Fluids Barriers CNS

Tocilizumab promotes repair of spinal cord injury by facilitating the restoration of tight junctions between vascular endothelial cells

托珠单抗通过促进血管内皮细胞间紧密连接的恢复促进脊髓损伤修复

Understanding molecular transport in the brain is critical to care and prevention of neurological disease and injury. A key question is whether transport occurs primarily by diffusion, or also by convection or dispersion. Dynamic contrast-enhanced (DCE-MRI) experiments have long reported solute transport in the brain that appears to be faster than diffusion alone, but this transport rate has not been quantified to a physically relevant value that can be compared to known diffusive rates of tracers.In this work, DCE-MRI experimental data is analyzed using subject-specific finite-element models to quantify transport in different anatomical regions across the whole mouse brain. The set of regional effective diffusivities ([Formula: see text]), a transport parameter combining all mechanisms of transport, that best represent the experimental data are determined and compared to apparent diffusivity ([Formula: see text]), the known rate of diffusion through brain tissue, to draw conclusions about dominant transport mechanisms in each region.In the perivascular regions of major arteries, [Formula: see text] for gadoteridol (550 Da) was over 10,000 times greater than [Formula: see text]. In the brain tissue, constituting interstitial space and the perivascular space of smaller blood vessels, [Formula: see text] was 10-25 times greater than [Formula: see text].The analysis concludes that convection is present throughout the brain. Convection is dominant in the perivascular space of major surface and branching arteries (Pe > 1000) and significant to large molecules (> 1 kDa) in the combined interstitial space and perivascular space of smaller vessels (not resolved by DCE-MRI). Importantly, this work supports perivascular convection along penetrating blood vessels.

Lori A. Ray

Martin Pike

Matthew Simon

Jeffrey J. Iliff

Jeffrey J. Heys

Quantitative analysis of macroscopic solute transport in the murine brain

小鼠脑内宏观溶质输运的定量分析

Abstract The vessels of the central nervous system (CNS) have unique barrier properties. The endothelial cells (ECs) which comprise the CNS vessels contribute to the barrier via strong tight junctions, specific transporters, and limited endocytosis which combine to protect the brain from toxins and maintains brain homeostasis. Blood–brain barrier (BBB) leakage is a serious secondary injury in various CNS disorders like stroke, brain tumors, and neurodegenerative disorders. Currently, there are no drugs or therapeutics available to treat specifically BBB damage after a brain injury. Growing knowledge in the field of epigenetics can enhance the understanding of gene level of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB. In this brief review, we summarize the epigenetic mechanisms or regulators that have a protective or disruptive role for components of BBB, along with the promising approaches to regain the integrity of BBB.

Stephanie A. Ihezie

Iny Elizebeth Mathew

Devin W. McBride

Ari Dienel

Spiros L. Blackburn

Peeyush Kumar Thankamani Pandit

Epigenetics in blood–brain barrier disruption

血液-脑屏障破坏中的表观遗传学

Abstract Background The choroid plexus functions as the blood-cerebrospinal fluid (CSF) barrier, plays an important role in CSF production and circulation, and has gained increased attention in light of the recent elucidation of CSF circulation dysfunction in neurodegenerative conditions. However, methods for routinely quantifying choroid plexus volume are suboptimal and require technical improvements and validation. Here, we propose three deep learning models that can segment the choroid plexus from commonly-acquired anatomical MRI data and report performance metrics and changes across the adult lifespan. Methods Fully convolutional neural networks were trained from 3D T 1 -weighted, 3D T 2 -weighted, and 2D T 2 -weighted FLAIR MRI using gold-standard manual segmentations in control and neurodegenerative participants across the lifespan (n = 50; age = 21–85 years). Dice coefficients, 95% Hausdorff distances, and area-under-curve (AUCs) were calculated for each model and compared to segmentations from FreeSurfer using two-tailed Wilcoxon tests (significance criteria: p &lt; 0.05 after false discovery rate multiple comparisons correction). Metrics were regressed against lateral ventricular volume using generalized linear models to assess model performance for varying levels of atrophy. Finally, models were applied to an expanded cohort of adult controls (n = 98; age = 21–89 years) to provide an exemplar of choroid plexus volumetry values across the lifespan. Results Deep learning results yielded Dice coefficient = 0.72, Hausdorff distance = 1.97 mm, AUC = 0.87 for T 1 -weighted MRI, Dice coefficient = 0.72, Hausdorff distance = 2.22 mm, AUC = 0.87 for T 2 -weighted MRI, and Dice coefficient = 0.74, Hausdorff distance = 1.69 mm, AUC = 0.87 for T 2 -weighted FLAIR MRI; values did not differ significantly between MRI sequences and were statistically improved compared to current commercially-available algorithms (p &lt; 0.001). The intraclass coefficients were 0.95, 0.95, and 0.96 between T 1 -weighted and T 2 -weighted FLAIR, T 1 -weighted and T 2 -weighted, and T 2 -weighted and T 2 -weighted FLAIR models, respectively. Mean lateral ventricle choroid plexus volume across all participants was 3.20 ± 1.4 cm 3 ; a significant, positive relationship (R 2 = 0.54-0.60) was observed between participant age and choroid plexus volume for all MRI sequences (p &lt; 0.001). Conclusions Findings support comparable performance in choroid plexus delineation between standard, clinically available, non-contrasted anatomical MRI sequences. The software embedding the evaluated models is freely available online and should provide a useful tool for the growing number of studies that desire to quantitatively evaluate choroid plexus structure and function ( https://github.com/hettk/chp_seg ).

Jarrod J. Eisma

Colin D. McKnight

Kilian Hett

Jason Elenberger

Caleb J. Han

Alexander K. Song

Ciaran Considine

Daniel O. Claassen

Manus J. Donahue

Deep learning segmentation of the choroid plexus from structural magnetic resonance imaging (MRI): validation and normative ranges across the adult lifespan

成人一生中结构磁共振成像（MRI）的脉络丛深度学习分割：验证与规范范围

Growing evidence suggests that for rodents, a substantial fraction of cerebrospinal fluid (CSF) drains by crossing the cribriform plate into the nasopharyngeal lymphatics, eventually reaching the cervical lymphatic vessels (CLVs). Disruption of this drainage pathway is associated with various neurological disorders.

Daehyun Kim

Jeffrey Tithof

Lumped parameter simulations of cervical lymphatic vessels: dynamics of murine cerebrospinal fluid efflux from the skull

颈淋巴管的集总参数模拟：小鼠脑脊液从颅内排出的动力学

The physiology of transient intracranial pressure (ICP) elevations (B waves), remains incompletely understood and appears to involve multiple mechanisms, including obstructive sleep apnea (OSA). Transient ICP elevations are associated with OSA and cyclic alternating pattern (CAP) metrics, suggesting a complex interplay between sleep fragmentation and ICP dynamics. Additionally, CAP metrics could complement standard OSA assessments, providing deeper insights into transient ICP fluctuations, particularly in conditions like normal-pressure hydrocephalus and idiopathic intracranial hypertension. Future studies should explore CAP-ICP interactions to elucidate their physiological and clinical implications.

Casper Schwartz Riedel

In response to Mutti et al. 2024 commentary on “Transient intracranial pressure elevations (B waves) associated with sleep apnea: the neglected role of cyclic alternating pattern”

回应Mutti等人2024年关于“与睡眠呼吸暂停相关的短暂颅内压升高（B波）：周期性交替模式被忽视的作用”的评论

Protein expression analysis of isolated brain microvessels provides valuable insights into the function of the blood-brain barrier (BBB). However, isolation of brain microvessels from human brain tissue, particularly in small quantities, poses significant challenges. This study presents a method for isolating brain microvessels from a small amount of frozen human brain tissue, adapting techniques from an established mouse brain capillary isolation method. Brain microvessel fractions were obtained from approximately 0.3 g of frozen human brain tissue (frontal cortex) using a bead homogenizer for homogenization, followed by purification with a combination of cell strainers and glass beads. Protein expression in the isolated human microvessel fractions and whole-brain lysates was analyzed by western blot and proteomic analysis. Microscopic imaging confirmed the successful isolation of brain microvessels from frozen human brain tissue. Protein quantification assays demonstrated that the microvessel fraction yielded sufficient protein for detailed expression analysis. Western blot analysis revealed an enrichment of BBB-selective proteins including multidrug resistance 1 (MDR1)/ATP-binding cassette sub-family B member 1 (ABCB1), glucose transporter protein type 1 (GLUT1)/solute carrier family 2 member 1 (SLC2A1), and claudin 5 (CLDN5), in the brain microvessel fraction compared to whole-brain lysates. Multiple reaction monitoring quantification of six BBB-selective proteins—MDR1, breast cancer resistance protein (BCRP)/ATP binding cassette subfamily G member 2 (ABCG2), GLUT1, monocarboxylate transporter 1 (MCT1)/solute carrier family 16 member 1 (SLC16A1), transferrin receptor, and CLDN5—revealed expression levels consistent with those observed in larger human brain samples. Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS)-based quantitative proteomics further demonstrated significant enrichment of human microvascular endothelial cells in the isolated fraction, corroborating the findings from mouse models. We successfully developed a method for isolation of brain microvessels from a small amount of frozen human brain tissue, facilitating detailed study of BBB proteome in aging or pathological conditions. This technique provides valuable insights into BBB dysfunction in central nervous system disorders and holds potential for improving brain-targeted drug delivery strategies.

Seiryo Ogata

Shingo Ito

Takeshi Masuda

Sumio Ohtsuki

Isolation method of brain microvessels from small frozen human brain tissue for blood-brain barrier protein expression analysis

从小块冷冻人脑组织中分离脑微血管以进行血脑屏障蛋白表达分析的方法

Hydrocephalus, an accumulation of cerebrospinal fluid (CSF) in the ventricles of the brain, is often treated via a shunt system to divert the excess CSF to a different compartment; if left untreated, it can lead to serious complications and permanent brain damage. It is estimated that one in every 500 people are born with hydrocephalus. Despite more than 60 years of concerted efforts, shunts still have the highest failure rate of any neurological device requiring follow-up shunt revision surgeries and contributing to the $2 billion cost of hydrocephalus care in the US alone. The absence of a tested and validated long-term in-vitro model that can incorporate clinically relevant parameters has limited hypothesis-driven studies and, in turn, limited our progress in understanding the mechanisms of shunt obstruction in hydrocephalus. Testing clinical parameters of flow, pressure, shear, catheter material, surface modifications, and others while optimizing for minimal protein, cellular, and blood interactions has yet to be done systematically for ventricular catheters. Several studies point to the need to not only understand how cells and tissues have occluded these shunt catheters but also how to stop the likely multi-faceted failure. For instance, studies show us that tissue occluding the ventricular catheter is primarily composed of proliferating astrocytes and cells of the macrophage lineage. Cell reactivity has been observed to follow flow gradients, with elevated levels of typically pro-inflammatory interleukin-6 produced under shear stress conditions greater than 0.5 dyne/[Formula: see text]. But also, that shear can shift cellular attachment. The Automated, In vitro Model for hydrocephalus research (AIMS), presented here, improves upon our previous long-term in vitro systems with specific goals of recapitulating bulk pulsatile cerebrospinal fluid (CSF) waveforms and steady-state flow directionality relevant to ventricular catheters used in hydrocephalus.

Ahmad Faryami

Adam Menkara

Shaheer Ajaz

Christopher Roberts

Ryan Jaroudi

Blake Gura

Tala Hussini

Carolyn A Harris

Recapitulation of physiologic and pathophysiologic pulsatile CSF flow in purpose-built high-throughput hydrocephalus bioreactors

生理性和病理性脉动脑脊液流动在专用高通量脑积水生物反应器中的再现

The importance of optimizing intrathecal drug delivery is highlighted by its potential to improve patient health outcomes. Findings from previous computational studies, based on an individual or a small group, may not be applicable to the wider population due to substantial geometric variability. Our study aims to circumvent this problem by evaluating an individual's cycle-averaged Lagrangian velocity field based on the geometry of their spinal subarachnoid space. It has been shown by Lawrence et al. (J Fluid Mech 861:679-720, 2019) that dominant physical mechanisms, such as steady streaming and Stokes drift, are key to facilitating mass transport within the spinal canal. In this study, we computationally modeled pulsatile cerebrospinal fluid flow fields and Lagrangian velocity field within the spinal subarachnoid space. Our findings highlight the essential role of minor structures, such as nerve roots, denticulate ligaments, and the wavy arachnoid membrane, in modulating flow and transport dynamics within the spinal subarachnoid space. We found that these structures can enhance fluid transport. We also emphasized the need for particle tracking in computational studies of mass transport within the spinal subarachnoid space. Our research illuminates the relationship between the geometry of the spinal canal and transport dynamics, characterized by a large upward cycle-averaged Lagrangian velocity zone in the wider region of the geometry, as opposed to a downward zone in the narrower region and areas close to the wall. This highlights the potential for optimizing intrathecal injection protocols by harnessing natural flow dynamics within the spinal canal.

Ziyu Wang

Mohammad Majidi

Chenji Li

Arezoo Ardekani

Numerical study of the effects of minor structures and mean velocity fields in the cerebrospinal fluid flow

脑脊液流动中小结构和平均速度场影响的数值研究

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Journal Impact	5.85
mbqgSu	NEUROSCIENCES(Q1)
xGGr6y	SCI Q1中科院 1 区

ISSN	2045-8118
h-index	65
hQoIdU	医学(1区)医学神经科学(2区)

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Fluids and Barriers of the CNS

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Tunneling nanotubes evoke pericyte/endothelial communication during normal and tumoral angiogenesis

Tocilizumab promotes repair of spinal cord injury by facilitating the restoration of tight junctions between vascular endothelial cells

Quantitative analysis of macroscopic solute transport in the murine brain

Epigenetics in blood–brain barrier disruption

Deep learning segmentation of the choroid plexus from structural magnetic resonance imaging (MRI): validation and normative ranges across the adult lifespan

Lumped parameter simulations of cervical lymphatic vessels: dynamics of murine cerebrospinal fluid efflux from the skull

In response to Mutti et al. 2024 commentary on “Transient intracranial pressure elevations (B waves) associated with sleep apnea: the neglected role of cyclic alternating pattern”

Isolation method of brain microvessels from small frozen human brain tissue for blood-brain barrier protein expression analysis

Recapitulation of physiologic and pathophysiologic pulsatile CSF flow in purpose-built high-throughput hydrocephalus bioreactors

Numerical study of the effects of minor structures and mean velocity fields in the cerebrospinal fluid flow