Fluids and Barriers of the CNS最新文献

Background: Known circadian variations in cerebrospinal fluid (CSF) flow and composition include fluctuations in electrolytes, hormones, and neurotransmitters. However, how commonly measured CSF constituents, such as protein and glucose, vary by time-of-day is understudied. Here, we identify and compare time-of-day differences in CSF protein and glucose from patients who underwent CSF collection during clinical care.

Methods: Patients with CSF collected between June 2018 and May 2023 at thirteen hospitals within our institution's health system were identified. Clinical, demographic and laboratory results were recorded. CSF results were divided into 1- and 4-hour intervals based on time-of-day and patient age. Patients were excluded if there was evidence of CSF infection, bleeding, as well as age criteria excluding neonates. One-way ANOVA with post-hoc Tukey was used to analyze differences between means.

Results: 15,272 patients underwent 26,397 CSF collection encounters. After exclusion, 8,210 CSF glucose and 10,103 CSF protein values remained. The CSF/blood glucose ratio showed time-of-day fluctuations; the mean ratio was higher from 00:00-04:00 (0.660), 04:00-08:00 (0.651), 16:00-20:00 (0.619), and 20:00-00:00 (0.633) than from 08:00-12:00 (0.588) and 12:00-16:00 (0.599). This pattern was also observed when dividing the time-of-day into 1-hour intervals and in every age cohort except patients 80 years and older. Children also exhibited time-of-day differences in CSF/blood glucose ratios, but the phase of their time-of-day pattern is shifted earlier to peak at 00:00-04:00. No clear time-of-day patterns were observed for CSF protein; however there was a significant association of age with CSF protein (R² = 0.2182). There were no meaningful differences in CSF protein by time-of-day after separating patients by age.

Conclusions: Higher CSF glucose from 00:00-08:00 and 16:00-00:00 compared to 08:00-16:00 suggests diurnal fluctuations which may be driven by a circadian rhythm. A higher CSF protein concentration was strongly associated with increasing age, without clear time-of-day variations. These results have implications for clinical interpretation and future research of the role of CSF in health and disease.

Background: Cerebrospinal fluid (CSF) clearance via the olfactory pathway is well-documented in animal models. However, results from in vivo human studies appear inconsistent. Studies using intrathecal (IT) Gadolinium-based contrast agents (GBCA) enhanced MRI showed minimal tracer pass-through from intracranial to extracranial olfactory regions such as the nasal mucosa. Conversely, human imaging studies using intravenous (IV) tracers showed significant enhancement in the nasal mucosa, suggesting CSF drainage through the cribriform plate. This research seeks to clarify these conflicting results from imaging studies using intrathecal and intravenous tracers, and to provide a better understanding of intravenous GBCA distribution in intracranial and extracranial olfactory regions, an important issue for studies using intravenous-GBCA-enhanced-MRI to investigate CSF clearance.

Methods: Dynamic-susceptibility-contrast-in-the-CSF (cDSC) MRI was applied to measure GBCA distribution in the CSF immediately and 4 h after intravenous administration in 25 healthy volunteers (48.9 ± 19.5 years; 14 females). A region-of-interest (ROI)-based and a voxel-based analysis were performed to measure GBCA concentration in intracranial and extracranial olfactory regions. Paired t-tests were used to compare pre- and post-GBCA signal changes.

Results: GBCA-induced signal changes were detected in all olfactory regions immediately and 4 h after intravenous GBCA administration. GBCA concentration was significantly greater (P < 0.01) in extracranial olfactory regions than intracranial olfactory regions. At 4 h post-GBCA, GBCA concentration decreased in extracranial olfactory regions compared to the immediate post-GBCA period, while it was comparable at both time points in intracranial olfactory regions.

Conclusions: Intravenous-GBCA-enhanced-MRI can detect GBCA distribution in the CSF space of olfactory regions in healthy subjects. The GBCA-induced CSF signal changes in intracranial olfactory regions were substantially smaller compared to extracranial olfactory regions. GBCA concentration in the CSF of intracranial olfactory regions was comparable to other intracranial regions. The significant GBCA-induced signal changes in extracranial olfactory regions may largely originate from peripheral blood supply when using intravenous tracers, which reflects lymphatic fluid circulation in the extracranial lymphatic system, and are not directly related to CSF clearance from the brain. Therefore, when using intravenous tracer-based imaging methods, it is critical to separate intracranial and extracranial regions in the analysis due to their different vascular supply.

Background: Adult-type diffuse gliomas are highly vascular malignant tumors of the central nervous system (CNS), classified according to the 2021 WHO CNS criteria. Their neovasculature arises through both angiogenesis and vascular co-option, generating heterogeneous microvascular patterns, often associated with microvascular proliferations (MVPs). The transition from an intact blood-brain barrier (BBB) to a dysfunctional blood-brain tumor barrier (BBTB) involves progressive disruption of the neurovascular unit (NVU), yet the phenotypic identity of tumor-associated endothelial cells (ECs) remains poorly characterized.

Methods: We investigated the endothelial phenotype in 22 adult-type diffuse gliomas (glioblastoma, astrocytoma grade 4 and 3, oligodendroglioma grade 3 and 2) by immunohistochemical analysis of two EC markers: P-glycoprotein (P-gp), a transporter associated with mature BBB phenotype, and CD146, an adhesion molecule linked to immature, mesenchymal-like ECs. Expression was assessed in the vascular endothelium, perivascular, and extravascular compartments using both qualitative evaluation and morphometric quantification on digital slides.

Results: Our findings revealed heterogeneous expression patterns of P-gp and CD146 among glioma subtypes. P-gp expression decreased progressively from oligodendrogliomas to glioblastomas, in line with increasing vascular dedifferentiation. Conversely, CD146 expression was higher in high-grade tumors, particularly in proliferating vessels and perivascular regions. These opposing trends reflected a gradual phenotypic shift from BBB-like to BBTB-like microvasculature, correlating with tumor histotype and grade.

Conclusion: P-gp and CD146 represent complementary markers of endothelial identity in gliomas and may serve as histopathological indicators of BBB integrity and tumor vascular remodeling. Their combined evaluation offers a novel insight into the BBB-BBTB transition and may support microvascular phenotyping as an adjunct criterion for glioma grading.

Neurogranin (Ng), a known regulator of neuronal Ca²⁺-calmodulin (CaM) signaling, is linked to Alzheimer's disease. Though well-studied in neurons, Ng is also expressed in brain vasculature, where its function remains unclear. To investigate Ng's role in brain microvascular endothelial cells, we defined its interactome using immunoprecipitation-mass spectrometry (IP-MS) under high- and low-Ca²⁺ conditions. Among 119 Ng-binding proteins, we discovered a novel interaction between Ng and MYH9, a key regulator of cytoskeletal remodeling. Ng-MYH9 binding was prominent in high Ca²⁺ and validated via CaM affinity pulldown and proximity ligation assays. Ng knockdown reduced F-actin levels, while MYH9 knockdown decreased both Ng and F-actin. Loss of Ng-MYH9 also impaired AKT-GSK3β signaling and elevated the endothelial activation marker VCAM1. Ng-null mice exhibited disrupted brain microvascular architecture and reduced MYH9 expression in endothelial cells. These findings reveal a novel Ng pathway promoting MYH9-dependent cytoskeletal remodeling and a potential role in maintaining blood-brain barrier integrity, a previously unrecognized function for Ng in brain health and Alzheimer's disease.

Background: Brain pericytes, the mural cells of cerebral microvessels, were long regarded as controversial, mainly due to their morphological and functional heterogeneity, plasticity, and variable expression of alpha-smooth muscle actin (α-SMA). However, they have recently emerged as a focal point in neuroscience research owing to their critical roles in regulating the blood-brain barrier (BBB), neuroinflammation, cerebral blood flow (CBF), and angiogenesis. In particular, the regulation of CBF and angiogenesis involves highly dynamic processes such as contraction and migration. By converting chemical energy into mechanical work, motor proteins, like myosin-through their interactions with intracellular filaments, primarily actin-play a crucial role in these processes.

Main body: In this review, we describe the contractile elements of pericytes, highlighting the relevance of α-SMA and myosin II isoforms containing the Myh11 and Myh9 heavy chains. In addition, we discuss recent advances in understanding how distinct pericyte subtypes contribute to mechanical force generation during the regulation of vessel diameter, pericyte migration, and the dynamic remodelling of their cellular processes. Furthermore, we highlight how ensheathing pericytes, which envelop the initial branches of the capillary bed and express high levels of α-SMA, initiate robust vasorelaxation during neurovascular coupling. In contrast, α-SMA-low capillary pericytes regulate basal vascular tone but also actively sense and respond to local glucose levels and neuronal activity. While ensheathing pericytes play a central role in sustained vasoconstriction following ischaemia, capillary pericytes are primarily responsible for secondary vasoconstrictive events during stroke.

Conclusions: Taken together, pericytes are dynamic cells capable of exerting diverse forms of mechanical force, playing essential roles in both physiological and pathological conditions. Eppur si muove-and yet it moves.

Biological barriers play a crucial role in maintaining tissue homeostasis across diverse animal taxa, from invertebrates to mammals. In the nervous system, they regulate ion balance, metabolic exchange, and immune protection, ensuring proper neuronal function. In arthropods, the blood-brain barrier (BBB) is primarily formed by the perineurium, consisting of perineurial and subperineurial glial cells that establish septate junctions to restrict diffusion. Cephalopods, such as octopuses and squids, possess two distinct BBBs: one formed by glial cells and another by pericytes, depending on the type of brain blood vessel. Similarly, in vertebrates such as sharks, skate, rays, and sturgeons, the BB is also formed by glial cells. In contrast, the BBBs of most vertebrates rely on endothelial tight junctions, although astrocytes and pericytes contribute significantly to BBB maintenance and function. Importantly, glial barriers also exist in vertebrates, including the blood-nerve barrier (BNB), and the blood-cerebrospinal fluid barrier (BCSFB). Despite structural differences, the molecular mechanisms governing barrier formation, function, and plasticity show remarkable evolutionary conservation between invertebrates and vertebrates. In this review, we examine the diversity of glial barriers, their structural and functional parallels, evolutionary origins, and the key molecular pathways that regulate their development.