Cerebrospinal Fluid Production Research Articles

Spontaneous intracranial hypotension in a patient without corpus callosum: A case report.

Spontaneous intracranial hypotension (SIH) is a well-established condition typically presenting with disabling orthostatic headache. Corpus callosum agenesis (CCA) is one of the most common human brain malformations with a wide spectrum of associated malformations, chromosomal abnormalities, and clinical syndromes. A 53-year-old woman presented with recurrent orthostatic headache for about 1 month. The head computed tomography examination of the patient showed CCA and the initial pressure of subsequent lumbar puncture was only 5 centimeters cerebrospinal fluid. Magnetic resonance imaging examination confirmed CCA with gray matter heterotopia. The final diagnose was SIH related headache with CCA. The patient's symptom improved after oral hydration, intravenous fluids, and bed rest. Favorable outcome was observed. Although this co-occurrence of SIH and CCA is probably coincidental, this finding suggests that the developmental malformations of the brain may lead to structural changes in brain tissue or disturbances in cerebrospinal fluid production and reflux, resulting in pathological changes over time.

Growth hormone therapy does not impact the development of intracranial hypertension in children with Chiari malformation.

Patients with Chiari malformation (CM) are prone to a variety of neurological sequelae, including benign intracranial hypertension (BIH). In these patients, BIH is attributed to impaired cerebrospinal fluid (CSF) flow due to anatomical abnormalities of the posterior fossa. Occasionally, patients with CM may require growth hormone therapy (GHT), which can increase the production of CSF. It is thought that patients with CM who undergo GHT are at high risk of BIH-associated symptoms (BIHAS). We describe the incidence of neurological symptoms in 34 patients with CM before and during GHT. The database of a pediatric endocrinology center was queried for patients with CM who received GHT from2010-22. Records were reviewed for adverse events. Demographic and radiological data were collected and analyzed. Patients with neoplastic disease, active inflammation, or acute trauma were excluded. CM diagnoses were independently assigned by a neuroradiology department. Patients were grouped based on the presence and nature ofsymptoms before and during GHT. Relationships between starting dose/BMI and occurrence of BIHAS/all GHT-associated symptoms were evaluated. GHT was not associated with new-onset or worsening of preexisting BIHAS in 33 out of 34 patients with CM. Five complex patients continued to have preexisting BIHAS, which did not worsen. Of the four patients who developed new-onset BIHAS during GHT, three patients' symptoms were attributed to other medical conditions. No patient permanently discontinued GHT due to BIHAS. Growth hormone therapy is likely a safe treatment in patients with Chiari malformation and is unlikely to cause BIHAS.

Role of Acetazolamide in Traumatic CSF Rhinorrhea and Otorrhea: A Randomized Controlled Trial.

Background Untreated cerebrospinal fluid (CSF) rhinorrhea and otorrhea can lead to adverse complications like meningitis and hence should not be overlooked. Acetazolamide reduces CSF production by 48%. The actual role of acetazolamide in the amelioration of traumatic CSF rhinorrhea and otorrhea is not clear as, till date, very few formal studies have been conducted. Aim of the study was to determine the role of acetazolamide in traumatic cerebrospinal fluid rhinorrhea and otorrhea. Materials and Methods A randomized controlled trial was conducted among 134 patients with head injuries presenting to the neurosurgery department of a tertiary care center in North India, with complaints of CSF rhinorrhea and otorrhea within 72 hours of traumatic injury. One-hundred thirty-four patients were randomized into intervention and control group. Comparative analysis was not possible in 58 patients as in due course they were either operated for head injury or lumbar drain was put due to excessive CSF leak; hence, forth comparative analysis was done in 76 patients. Out of these 76 patients, 44 patients belonged to the intervention group (Acetazolamide given) and 32 belong to the control group (Acetazolamide not given). The day of the stoppage of CSF Leak was the main endpoint of this study. Result Majority of the patients were in the age group of 21 to 30 years and were predominantly males. Road traffic accident was observed in 84 (75%) patients. There was no statistically significant difference noted in the mean number of days of CSF leak whether acetazolamide was given or not ( p = 0.344). The complication associated with CSF leak was meningitis. The percentage of patients developing meningitis was more after lumber drain insertion. Conclusion In our study, there was no advantage of adding acetazolamide to the conservative management of traumatic CSF leak. Therefore, the practice of routinely giving acetazolamide should be reconsidered.

The circadian clock in the choroid plexus drives rhythms in multiple cellular processes under the control of the suprachiasmatic nucleus

Choroid plexus (ChP), the brain structure primarily responsible for cerebrospinal fluid production, contains a robust circadian clock, whose role remains to be elucidated. The aim of our study was to [1] identify rhythmically controlled cellular processes in the mouse ChP and [2] assess the role and nature of signals derived from the master clock in the suprachiasmatic nuclei (SCN) that control ChP rhythms. To accomplish this goal, we used various mouse models (WT, mPer2Luc, ChP-specific Bmal1 knockout) and combined multiple experimental approaches, including surgical lesion of the SCN (SCNx), time-resolved transcriptomics, and single cell luminescence microscopy. In ChP of control (Ctrl) mice collected every 4 h over 2 circadian cycles in darkness, we found that the ChP clock regulates many processes, including the cerebrospinal fluid circadian secretome, precisely times endoplasmic reticulum stress response, and controls genes involved in neurodegenerative diseases (Alzheimer’s disease, Huntington’s disease, and frontotemporal dementia). In ChP of SCNx mice, the rhythmicity detected in vivo and ex vivo was severely dampened to a comparable extent as in mice with ChP-specific Bmal1 knockout, and the dampened cellular rhythms were restored by daily injections of dexamethasone in mice. Our data demonstrate that the ChP clock controls tissue-specific gene expression and is strongly dependent on the presence of a functional connection with the SCN. The results may contribute to the search for a novel link between ChP clock disruption and impaired brain health.

TRPV4 Antagonist Treatment of Hydrocephalus Causes Cell and Molecular Changes in Multiple Brain Cell Types

Hydrocephalus is defined by cerebrospinal fluid (CSF) accumulation in the brain’s ventricles causing ventriculomegaly, an imbalance in CSF secretion, flow, and/or absorption. Treatments for hydrocephalus include invasive surgical procedures, which commonly fail throughout a patient’s life. Transient receptor potential vanilloid member 4 (TRPV4) is a mechanosensitive cation channel implicated in osmotic regulation. Our laboratory found that a TRPV4 antagonist, RN1734, ameliorates hydrocephalus in a rat model of congenital hydrocephalus. It was hypothesized that treatment slowed production of CSF by targeting choroid plexus (CP), a contiguous layer of tightly regulated epithelial cells, that is responsible for CSF production. However, hydrocephalus pathology can have various effects on the brain. This study focuses on changes occurring in CP epithelial cells (CPe) and glia, which have roles in brain-barrier maintenance and brain fluid/electrolyte regulation. Interestingly, CPe and glia contain many of the same channels and transporters, including TRPV4, that are important in regulating both CSF and brain interstitial fluid. These cells contain aquaporins (AQP), AQP1 in CPe, and AQP4 in glia. AQPs have been implicated in diseases associated with fluid regulation and may interact with TRPV4. We hypothesize that TRPV4 and AQPs are important in hydrocephalus pathology, and that changes may be attenuated with RN1734 treatment. A point mutation in TMEM67 results in hydrocephalus (hydro). Changes in cell morphology, gene transcription, protein expression, localization of TRPV4, AQP1, and AQP4 were observed. Postnatal day 15 (P15) untreated (unt) and RN1734-treated (RN;2mg/ml DMSO; 4mg/kg intraperitoneal injection daily P7-P14) wildtype and mutant ( Tmem67−/−) rats were utilized in this study. CPe and periventricular (PV) glia were visualized using fluorescent immunohistochemistry (IHC) of GFAP and a plasma membrane marker. Cell volume of CPe’s and process morphology of glia were altered in hydro rats. RN returned these changes to relatively normal in CPe, but not glia. Next, we used IHC to examine localization of TRPV4 and the AQPs. Increased immunoreactivity of TRPV4 and AQP1 was observed in CPe of unt and RN Tmem67−/− rats. AQP4 and TRPV4 immunoreactivity increased in the subventricular zone and PV white matter of hydro rats. TRPV4 immunoreactivity, but not AQP4, was normalized with RN. We then utilized RTqPCR to inspect transcriptional changes. The data showed increased AQP1 and decreased TRPV4 mRNA in PV cortex and CP of unt and RN Tmem67−/− rats. Previous data from our laboratory found no change in TRPV4 protein in unt Tmem67−/− CPe, but we were curious about AQP expression. The amount of AQP1 protein was increased in the CP of unt and RN Tmem67−/− rats. In PV cortex, AQP4, but not TRPV4, protein was increased in hydro rats. With RN, AQP4 protein was not normalized. In summary, TRPV4 changes in the Tmem67−/− rats returned to normal with RN, glial morphology and AQP changes did not. This may indicate residual inflammation in the Tmem67−/− rats, which we aim to address in future studies. To further elucidate TRPV4’s role in hydrocephalus pathology, future studies will explore post-translational and membrane localization changes. Overall, investigating cell and molecular changes that occur in hydrocephalus will help find better pharmacological targets for this disease. Funding: United States Department of Defense Congressionally Directed Medical Research Program Award; Hydrocephalus Association. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Role of Phase-Contrast MRI in Diagnosing Cerebrospinal Fluid Flow Abnormalities.

Background Cerebrospinal fluid (CSF) dynamics play a crucial role in maintaining the homeostasis of the central nervous system (CNS). Any disruption in CSF flow can lead to various congenital and acquired conditions, impacting neurological function and overall health. This study aims to analyze the significance of phase-contrast MRI in evaluating abnormalities in CSF flow and its diagnostic utility in various CSF-related disorders. Phase contrast MRIhas emerged as a valuable tool for evaluating CSF dynamics non-invasively by examining CSF flow characteristics such as pulsatile flow patterns, hyperdynamic or hypodynamic flow, and disruptions in CSF circulation. Alterations in CSF pulsatility and stroke volume can indicate changes in intracranial compliance, vascular resistance, or CSF production and absorption rates. The findings of this study will advance our understanding of CSF physiology and its relevance in neurological pathologies, potentially leading to improved patient outcomes and management approaches. Materials and methods The study involved 36 patients and was conducted as an observational, prospective study over 18 months (October 2020 to March 2022) at the Department of Radiology, Saveetha Medical College and Hospital, Chennai. We utilized a 1.5 T Philips Multiva MRI scanner by Philips Healthcare in Amsterdam, Netherlands.The study included patients with suspected CSF flow abnormalities and abnormal MRI findings (normal pressure hydrocephalus (NPH), age-related brain atrophy, aqueduct stenosis (AS), Chiari malformation type 1, syringomyelia, or arachnoid cyst), alongside control exhibiting normal neurological symptoms and MRI results. Exclusions involved individuals with febrile seizures, neurological diseases, cerebrovascular accidents, anti-convulsive medication use, cardiac arrhythmia, or MRI contraindications. Post-processing involved analyzing stroke volume (SV), peak systolic velocity (PSV), end diastolic velocity (EDV), and mean flux. Statistical analysis was conducted using the StatisticalPackage for the Social Sciences (IBMSPSSStatisticsforWindows,IBMCorp., Version 24.0, Armonk,NY), employing the χ2-test for categorical variables and nonparametric tests like Mann-Whitney U and Kruskal-Wallis H-tests for quantitative variables. A p-value < 0.05 was considered significant. Results The 36 patients, aged 1 to 80 years, were referred by the neurology department and categorized into four subgroups based on clinical history and conventional MRI findings: NPH, AS, age-related brain atrophy, and a normal control group. MRI CSF flowmetry evaluation focused on PSV, PDV, and SV. We found peak diastolic velocity (PDV), PSV, and average blood velocity (ABV) to be significantly higher in NPH compared to the control group (PSV, EDV, and SV: 9.96 +/- 1.73, 4.72 +/- 0.62, and 63 +/- 12.88 for NPH versus 4.8 +/- 0.39, 3.21 +/- 0.55, and 20.72 +/- 5.7 for control, respectively; p = 0.000). Conversely, patients with age-related brain atrophy and AS exhibited lower values (1.6 +/- 0.44, 1.13 +/- 0.09, and 6.33 +/- 2.08 for AS, and 2.07 +/- 0.09, 1.62 +/- 0.33, and 6.8 +/- 2.16 for age-related brain atrophy versus control; p = 0.002). Conclusion MRI CSF flowmetry emerges as a rapid, accurate, and non-invasive diagnostic tool for various neurological disorders associated with abnormal CSF flow. Additionally, this technique may aid in selecting appropriate treatment strategies.

Transporters, Ion Channels, and Junctional Proteins in Choroid Plexus Epithelial Cells.

The choroid plexus (CP) plays significant roles in secreting cerebrospinal fluid (CSF) and forming circadian rhythms. A monolayer of epithelial cells with tight and adherens junctions of CP forms the blood-CSF barrier to control the movement of substances between the blood and ventricles, as microvessels in the stroma of CP have fenestrations in endothelial cells. CP epithelial cells are equipped with several kinds of transporters and ion channels to transport nutrient substances and secrete CSF. In addition, junctional components also contribute to CSF production as well as blood-CSF barrier formation. However, it remains unclear how junctional components as well as transporters and ion channels contribute to the pathogenesis of neurodegenerative disorders. In this manuscript, recent findings regarding the distribution and significance of transporters, ion channels, and junctional proteins in CP epithelial cells are introduced, and how changes in expression of their epithelial proteins contribute to the pathophysiology of brain disorders are reviewed.

Ventriculo – Gallbladder shunt

Abstract Introduction: Permanent liquor diversion is associated with a high risk of failure and often requires re-intervention. The ventriculo-gallbladder shunt (VGS) has been recognized as a last-resort alternative for treating hydrocephalus when the peritoneum or other distal sites are no longer suitable for receiving shunts. This article aims to report a case from a neurosurgery referral service in Brazil and review the literature on this issue. Methods: A systematic literature review was conducted in accordance with the PRISMA statement. The PubMed, Embase, and Web of Science databases were searched for data screening and extraction. The reported case was conducted with ethical approval from the neurosurgical hospital's ethics committee. Results: G.B.S, male, 43 years old, no comorbidities, who has been dealing with a 12-year history of hydrocephalus, with post-surgical chronic fungal meningitis. Two years ago, he underwent a ventriculoatrial shunt (VAS) placement due to multiple ventriculoperitoneal shunt (VPS) failures. Endocarditis was suspected, and the VAS was removed. As an alternative, VGS was implanted 6 months ago, and since then, there has been no need for a new system review. The gallbladder has an absorptive capacity of 1500 cc of liquid daily, which is more than the normal daily production of cerebrospinal fluid (CSF). Therefore, it is a good alternative when the ventriculoperitoneal shunt is not feasible due to postsurgical peritoneal adhesions or when there are contraindications for ventriculoatrial shunts. Conclusion: VGS is an alternative for patients who cannot undergo the most common surgical interventions, such as VPS. Keywords: Ventriculo-gallbladder; Shunt; Hydrocephalus; Ventriculo-vesicular; Gallbladder.

Patient-specific automated cerebrospinal fluid pressure control to augment spinal wound closure: a case series using the LiquoGuard®

Objective Spinal cerebrospinal fluid (CSF) leaks are common, and their management is heterogeneous. For high-flow leaks, numerous studies advocate for primary dural repair and CSF diversion. The LiquoGuard7® allows automated and precise pressure and volume control, and calculation of patient-specific CSF production rate (prCSF), which is hypothesized to be increased in the context of durotomies and CSF leaks. Methods This single-centre illustrative case series included patients undergoing complex spinal surgery where: 1) a high flow intra-operative and/or post-operative CSF leak was expected and 2) lumbar CSF drainage was performed using a LiquoGuard7®. CSF diversion was tailored to prCSF for each patient, combined with layered spinal wound closure. Results Three patients were included, with a variety of pathologies: T7/T8 disc prolapse, T8-T9 meningioma, and T4-T5 metastatic spinal cord compression. The first two patients underwent CSF diversion to prevent post-op CSF leak, whilst the third required this in response to post-op CSF leak. CSF hyperproduction was evident in all cases (mean >/=140ml/hr). With patient-specific CSF diversion regimes, no cases required further intervention for CSF fistulae repair (including for pleural CSF effusion), wound breakdown or infection. Conclusions Patient-specific cerebrospinal fluid drainage may be a useful tool in the management of high-flow intra-operative and post-operative CSF leaks during complex spinal surgery. These systems may reduce post-operative CSF leakage from the wound or into adjacent body cavities. Further larger studies are needed to evaluate the comparative benefits and cost-effectiveness of this approach.

Which Theory of Cerebrospinal Fluid Production and Absorption Do Neurosurgeons Teach to Medical Students? Survey from Medical Universities in Japan, 2022.

Several new studies have been conducted on cerebrospinal fluid (CSF) dynamics. Our educational guidelines, the Model Core Curriculum for Medical University, recommend access to the best current information. However, we do not know whether or when to introduce changes to this concept.We surveyed which theory of CSF dynamics taught to students by neurosurgeons. The old theory is the bulk flow theory, and the new theory explains that CSF is produced from the choroid plexus and capillaries; CSF then pulsates and drains into the venous and lymphatic systems through newly discovered pathways.Old and new theories were taught to 64.8% and 27.0% of students, respectively. The reason for teaching the old theory was to help them understand the pathogenesis of noncommunicating hydrocephalus (77.1%), whereas the reason for teaching the new theory was to teach the latest knowledge (40.0%). Physicians who wished to teach the new theory in the near future accounted for 47.3%, which was higher than those who would teach the new theory in 2022 (27.0%), and those who still wished to teach the old theory in the near future accounted for 43.2%.An education policy on CSF dynamics will be established when we interpret ventricular enlargement and its improvement by third ventriculostomy in noncommunicating hydrocephalus based on the new theory. The distributed answers in the survey shared that it is difficult to teach about CSF dynamics and provided an opportunity to discuss these issues.

Investigation of the choroid plexus implication in Alzheimer’s disease pathophysiology using human proteomics and mouse transcriptomics

AbstractBackgroundThe choroid plexus (CP) is responsible for the production of cerebrospinal fluid (CSF), transport of proteins to the CSF and clearance of proteins from the CSF. The CP becomes compromised during aging, which is exacerbated in AD. Nonetheless, the relation between CP and AD pathophysiology remains unclear. We aim to investigate the pathophysiology underlying the CP involvement in AD, utilizing human CSF proteomics and mouse CP transcriptomics.MethodWe included 526 individuals from EMIF‐AD MBD, St Louis Knight ADRC and Maastricht BB‐ACL studies. Based on CSF Aβ1‐42 (A, data‐driven cut‐offs), individuals were classified as controls (cognitively normal (CN) A‐, n = 171) or as amyloid‐positive (CN A+, n = 120; mild cognitive impairment (MCI) A+, n = 154; AD A+, n = 81). CSF proteomic data were generated using TMT spectrometry and protein concentrations were compared using ANOVA adjusted for age and sex. Transcriptomic was performed in CP tissue of APPNL‐G‐F (n = 17) and wild‐type C57BL/6J (n = 17) mice using Illumina RNA‐Seq and differential expression analysis was conducted. Next, Gene Ontology and Ingenuity Pathway analyses were performed. For proteomics, high expression of proteins in the CP was identified based on Allen Brain Atlas and the R package ABAEnrichment.ResultIn CN A+, 51 proteins were increased and 21 decreased relative to controls. Out of those increased proteins, 57% were enriched for expression in the CP (ABAEnrichment P&lt;0.001, Figure 1) and were associated with lysosomes and the CLEAR pathway, extracellular matrix and coagulation. A similar pattern was observed for both MCI A+ and AD A+ compared to controls, with a significant percentage of increased proteins enriched for expression in the CP (22 to 30%), which are related to lysosomes and the CLEAR pathway, extracellular matrix and coagulation. In APPNL‐G‐F compared to wild‐type mice, CP transcriptomics revealed 313 upregulated and 198 downregulated genes (Figure 2). The upregulated genes were also associated with the lysosomes and the CLEAR pathway, as well as energy metabolism and lipids.ConclusionHuman proteomics and mice transcriptomics studies suggest an association between amyloid pathology, CP functioning and lysosomes. Dysfunction of lysosomes in AD could relate to compromised clearing events. This is important for future research and AD treatment development.

Near-Infrared Fluorescence Tomography and Imaging of Ventricular Cerebrospinal Fluid Flow and Extracranial Outflow in Non-Human Primates.

The role of the lymphatics in the clearance of cerebrospinal fluid (CSF) from the brain has been implicated in multiple neurodegenerative conditions. In premature infants, intraventricular hemorrhage causes increased CSF production and, if clearance is impeded, hydrocephalus and severe developmental disabilities can result. In this work, we developed and deployed near-infrared fluorescence (NIRF) tomography and imaging to assess CSF ventricular dynamics and extracranial outflow in similarly sized, intact non-human primates (NHP) following microdose of indocyanine green (ICG) administered to the right lateral ventricle. Fluorescence optical tomography measurements were made by delivering ~10 mW of 785 nm light to the scalp by sequential illumination of 8 fiber optics and imaging the 830 nm emission light collected from 22 fibers using a gallium arsenide intensified, charge coupled device. Acquisition times were 16 seconds. Image reconstruction used the diffusion approximation and hard-priors obtained from MRI to enable dynamic mapping of ICG-laden CSF ventricular dynamics and drainage into the subarachnoid space (SAS) of NHPs. Subsequent, planar NIRF imaging of the scalp confirmed extracranial efflux into SAS and abdominal imaging showed ICG clearance through the hepatobiliary system. Necropsy confirmed imaging results and showed that deep cervical lymph nodes were the routes of extracranial CSF egress. The results confirm the ability to use trace doses of ICG to monitor ventricular CSF dynamics and extracranial outflow in NHP. The techniques may also be feasible for similarly-sized infants and children who may suffer impairment of CSF outflow due to intraventricular hemorrhage.

Transient ischemic stroke triggers sustained damage of the choroid plexus blood-CSF barrier.

Neuroinflammation is a pathological event associated with many neurological disorders, including dementia and stroke. The choroid plexus (ChP) is a key structure in the ventricles of the brain that secretes cerebrospinal fluid (CSF), forms a blood-CSF barrier, and responds to disease conditions by recruiting immune cells and maintaining an immune microenvironment in the brain. Despite these critical roles, the exact structural and functional changes to the ChP over post-stroke time remain to be elucidated. We induced ischemic stroke in C57BL/6J mice via transient middle cerebral artery occlusion which led to reduction of cerebral blood flow and infarct stroke. At 1-7 days post-stroke, we detected time-dependent increase in the ChP blood-CSF barrier permeability to albumin, tight-junction damage, and dynamic changes of SPAK-NKCC1 protein complex, a key ion transport regulatory system for CSF production and clearance. A transient loss of SPAK protein complex but increased phosphorylation of the SPAK-NKCC1 complex was observed in both lateral ventricle ChPs. Most interestingly, stroke also triggered elevation of proinflammatory Lcn2 mRNA and its protein as well as infiltration of anti-inflammatory myeloid cells in ChP at day 5 post-stroke. These findings demonstrate that ischemic strokes cause significant damage to the ChP blood-CSF barrier, contributing to neuroinflammation in the subacute stage.

Choroid plexus mast cells drive tumor-associated hydrocephalus

Tumor-associated hydrocephalus (TAH) is a common and lethal complication of brain metastases. Although other factors beyond mechanical obstructions have been suggested, the exact mechanisms are unknown. Using single-nucleus RNA sequencing and spatial transcriptomics, we find that a distinct population of mast cells locate in the choroid plexus and dramatically increase during TAH. Genetic fate tracing and intracranial mast-cell-specific tryptase knockout showed that choroid plexus mast cells (CPMCs) disrupt cilia of choroid plexus epithelia via the tryptase-PAR2-FoxJ1 pathway and consequently increase cerebrospinal fluid production. Mast cells are also found in the human choroid plexus. Levels of tryptase in cerebrospinal fluid are closely associated with clinical severity of TAH. BMS-262084, an inhibitor of tryptase, can cross the blood-brain barrier, inhibit TAH invivo, and alleviate mast-cell-induced damage of epithelial cilia in a human pluripotent stem-cell-derived choroid plexus organoid model. Collectively, we uncover the function of CPMCs and provide an attractive therapy for TAH.

E-Cadherin Is Expressed in Epithelial Cells of the Choroid Plexus in Human and Mouse Brains.

Evidence showing the functional significance of the choroid plexus is accumulating. Epithelial cells with tight and adherens junctions of the choroid plexus play important roles in cerebrospinal fluid production and circadian rhythm formation. Although specific types of cadherin expressed in adherens junctions of choroid plexus epithelium (CPE) have been examined, they remained uncertain. Recent mass spectrometry and immunolocalization analysis revealed that non-epithelial cadherins, P- and N-cadherins, are expressed in the lateral membrane of CPE, whereas E-cadherin expression has not been confirmed in CPE of humans or mice. In this study, we examined E-cadherin expression in CPE of mice and humans by RT-PCR, immunohistochemical-, and Western blotting analyses. We confirmed, by using RT-PCR analysis, the mRNA expression of E-cadherin in the choroid plexus of mice. The immunohistochemical expression of E-cadherin was noted in the lateral membrane of CPE of mice and humans. We further confirmed, in Western blotting, the specific immunoreactivity for E-cadherin. Immunohistochemically, the expression of E- and N-cadherins or vimentin was unevenly distributed in some CPE, whereas that of E- and P-cadherins or β-catenin frequently co-existed in other CPE. These findings indicate that E-cadherin is expressed in the lateral membrane of CPE, possibly correlated with the expression of other cadherins and cytoplasmic proteins.

Bulat-Klarica-Oreskovic Hypothesis: A Comprehensive Review.

Classical theories of cerebrospinal fluid (CSF) production and flow are taught throughout medical education. The idea that CSF is produced and/or filtered by the choroid plexus and flows in one direction throughout the ventricular system has been a largely accepted thesis. However, modern studies have called into question the validity of this hypothesis, suggesting thatCSF does not move unidirectionallybut rather is driven by microvessel contractions in a to-and-fro manner throughout the cerebrospinal system. Moreover, new insights suggest that in addition to CSF production, the exchange of fluids and proteins between the cortical vasculature and the interstitium may function as the brain's version of a lymphatic system. This comprehensive review provides evidence for a different framework of CSF flow. One that includes perivascular pulsations that push CSF back and forth, allowing exchange between the CSF and interstitium, and with CSF production occurring throughout the cerebrospinal system. These findings could be revolutionary in understanding the pathophysiology of CSF flowand in the treatment of pathologies such as intracranial hypertension, hydrocephalus, Alzheimer's disease, and many others.

Impact of continuous-flow mechanical circulatory support on cerebrospinal fluid motility.

Mechanical circulatory support (MCS), including ventricular assist devices (VADs), have emerged as promising therapeutic alternatives for end-stage congestive heart failure (CHF). The latest generation of these devices are continuous flow (CF) blood pumps. While there have been demonstrated benefits to patient outcomes due to CF-MCS, there continue to be significant clinical challenges. Research to-date has concentrated on mitigating thromboembolic risk (stroke), while the downstream impact of CF-MCS on the cerebrospinal fluid (CSF) flow has not been well investigated. Disturbances in the CSF pressure and flow patterns are known to be associated with neurologic impairment and diseased states. Thus, here we seek to develop an understanding of the pathophysiologic consequences of CF-MCS on CSF dynamics. We built and validated a computational framework using lumped parameter modeling of cardiovascular, cerebrovascular physics, CSF dynamics, and autoregulation. A sensitivity analysis was performed to confirm robustness of the modeling framework. Then, we characterized the impact of CF-MCS on the CSF and investigated cardiovascular conditions of healthy and end-stage heart failure. Modeling results demonstrated appropriate hemodynamics and indicated that CSF pressure depends on blood flow pulsatility more than CSF flow. An acute equilibrium between CSF production and absorption was observed in the CF-MCS case, characterized by CSF pressure remaining elevated, and CSF flow rates remaining below healthy, but higher than CHF states. This research has advanced our understanding of the impact of CF-MCS on CSF dynamics and cerebral hemodynamics.

The relationship between AQP1 expression in the subventricular zone and severity of hydrocephalus in Rattus Norvegicus strain Sprague-Dawley rats

Link of Video Abstract: https://youtu.be/pWRyUuqXX7g Background: Hydrocephalus is a condition of dilation of the ventricles caused by disturbances production, distribution, or absorption of cerebrospinal fluid (CSF). One of the integral membrane proteins identified in facilitating water transport across the plasma membrane is aquaporin-1 (AQP1), which is frequently found in the plexus choroid. However, theoretically also transports water to the subventricular zone (SVZ) with an unknown mechanism. AQP1 expression will be raised in SVZ under hydrocephalus conditions. This study aims to evaluate the relationship between the severity of hydrocephalus and AQP1 levels in SVZ. Methods: This research was conducted in an experimental design using Rattus Norvegicus rats of the Sprague-Dawley strain, which were injected with kaolin to create a hydrocephalus model. The study included 24 rats, divided into four groups of six each: the control group and the hydrocephalus induction group on day 7, day 14, and day 21. AQP1 expression was observed using immunohistochemical staining and counted semi-quantitatively. Results: The average AQP1 expression increased with observation time in the rat model in each group. The ANOVA test showed a significant difference between the four study groups (p=0.001). The correlation showed a statistically significant difference (p=0.000). The results showed an increased expression of the SVZ with a higher severity of hydrocephalus. Conclusion: The severity of hydrocephalus and AQP1 levels in SVZ are correlated, with the latter being higher, the more severe the degree of hydrocephalus.

SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission.

SLC4A10 is a plasma-membrane bound transporter that utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of CSF. Using next generation sequencing on samples from five unrelated families encompassing nine affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorder including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioural abnormalities including delayed habituation and alterations in the two-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggest an important role of SLC4A10 in the production of the CSF. However, it is notable that despite diverse roles of the CSF in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed that in neurons, SLC4A10 localizes to inhibitory, but not excitatory, presynapses. These findings are supported by our functional studies, which show the release of the inhibitory neurotransmitter GABA is compromised in Slc4a10-/- mice, while the release of the excitatory neurotransmitter glutamate is preserved. Manipulation of intracellular pH partially rescues GABA release. Together our studies define a novel neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 and highlight the importance of further analyses of the consequences of SLC4A10 loss-of-function for brain development, synaptic transmission and network properties.

Spontaneously hypertensive rats can become hydrocephalic despite undisturbed secretion and drainage of cerebrospinal fluid

BackgroundHydrocephalus constitutes a complex neurological condition of heterogeneous origin characterized by excessive cerebrospinal fluid (CSF) accumulation within the brain ventricles. The condition may dangerously elevate the intracranial pressure (ICP) and cause severe neurological impairments. Pharmacotherapies are currently unavailable and treatment options remain limited to surgical CSF diversion, which follows from our incomplete understanding of the hydrocephalus pathogenesis. Here, we aimed to elucidate the molecular mechanisms underlying development of hydrocephalus in spontaneously hypertensive rats (SHRs), which develop non-obstructive hydrocephalus without the need for surgical induction.MethodsMagnetic resonance imaging was employed to delineate brain and CSF volumes in SHRs and control Wistar-Kyoto (WKY) rats. Brain water content was determined from wet and dry brain weights. CSF dynamics related to hydrocephalus formation in SHRs were explored in vivo by quantifying CSF production rates, ICP, and CSF outflow resistance. Associated choroid plexus alterations were elucidated with immunofluorescence, western blotting, and through use of an ex vivo radio-isotope flux assay.ResultsSHRs displayed brain water accumulation and enlarged lateral ventricles, in part compensated for by a smaller brain volume. The SHR choroid plexus demonstrated increased phosphorylation of the Na+/K+/2Cl− cotransporter NKCC1, a key contributor to choroid plexus CSF secretion. However, neither CSF production rate, ICP, nor CSF outflow resistance appeared elevated in SHRs when compared to WKY rats.ConclusionHydrocephalus development in SHRs does not associate with elevated ICP and does not require increased CSF secretion or inefficient CSF drainage. SHR hydrocephalus thus represents a type of hydrocephalus that is not life threatening and that occurs by unknown disturbances to the CSF dynamics.