Cerebrospinal Fluid Production Research Articles

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.

Cerebrospinal fluid production rate in various pathological conditions: a preliminary study

IntroductionThe cerebrospinal fluid (CSF) production rate in humans is not clearly defined but is estimated to be 18–24 ml/h (Trevisi et al Croat Med J 55(4):377–387 (24); Casey and Vries Childs Nerv Syst 5(5):332–334 (8)). A frequent clinical observation is that patients often drain higher volumes of CSF than can be explained by the assumed ‘normal’ CSF production rate (PRcsf). In the National Hospital for Neurology and Neurosurgery PRcsf was recorded in a variety of common neurosurgical pathologies using LiquoGuard7, an automated peristaltic pump that accurately controls CSF drainage and maintains a pre-set CSF pressure.MethodsA prospective observational study was performed from September 2021 onwards, on all patients in the National Hospital for Neurology and Neurosurgery who required CSF drainage as part of their ongoing treatment. The external drain was connected to a LiquoGuard7 pump (Möller Medical GmbH, Fulda, Germany), and the internal software of LiquoGuard7 was used to measure PRcsf. Statistical analysis used SPSS (version 25.0, IBM) by paired t test, comparing measured rates to hypothetical ‘normal’ CSF production rates calculated and published by Ekstedt (16–34ml/h) (Ekstedt J Neurol Neurosurg Psychiatry 41(4):345–353 (14)), assuming a similar distribution.ResultsPRcsf was calculated in 164 patients. Suspected normal pressure hydrocephalus (n=41): PRcsf of 79ml/h±20SD (p<0.0001). Post-surgical CSF leak (n=26): PRcsf of 90ml/h±20SD (p<0.0001). Subarachnoid haemorrhage (n=34): PRcsf of 143ml/h±9SD (p<0.0001). Intracerebral haemorrhage (n=22): PRcsf of 137ml/h±20SD (p<0.0001). Spinal lesions (n=7): PRcsf of 130ml/h±20SD (p<0.0032). Pituitary adenomas (n=10): PRcsf of 29 ml/h±9SD (p<0.049). Idiopathic intracranial hypertension (n=15): PRcsf of 86ml/h±10SD (p<0.0001). Decompensated long-standing overt ventriculomegaly (n=4): PRcsf of 65ml/h±10SD (p<0.0001). Cerebral infection (n=5): PRcsf of 90ml/h±20SD (p<0.0001).ConclusionNet CSF production rate may be higher than expected in many conditions, as measured with new device LiquoGuard7 through the study of net flow rate, which may have implications for clinical decisions on CSF diversion. The conventional understanding of CSF production and circulation does not explain the findings of this study. More extensive studies are needed to validate this technique.

Nocturnal increase in cerebrospinal fluid secretion as a circadian regulator of intracranial pressure

BackgroundIt is crucial to maintain the intracranial pressure (ICP) within the physiological range to ensure proper brain function. The ICP may fluctuate during the light-dark phase cycle, complicating diagnosis and treatment choice in patients with pressure-related disorders. Such ICP fluctuations may originate in circadian or sleep-wake cycle-mediated modulation of cerebrospinal fluid (CSF) flow dynamics, which in addition could support diurnal regulation of brain waste clearance.MethodsICP was monitored continuously in patients who underwent placement of an external ventricular drain (EVD) and by telemetric monitoring in experimental rats. CSF was collected via the EVD in patients and the rodent CSF secretion rate determined by in vivo experimentation. Rodent choroid plexus transporter transcripts were quantified with RNAseq and transport activity with ex vivo isotope transport assays.ResultsWe demonstrated that ICP increases by 30% in the dark phase in both species, independently of vascular parameters. This increase aligns with elevated CSF collection in patients (12%) and CSF production rate in rats (20%), the latter obtained with the ventriculo-cisternal perfusion assay. The dark-phase increase in CSF secretion in rats was, in part, assigned to increased transport activity of the choroid plexus Na+,K+,2Cl- cotransporter (NKCC1), which is implicated in CSF secretion by this tissue.ConclusionCSF secretion, and thus ICP, increases in the dark phase in humans and rats, irrespective of their diurnal/nocturnal activity preference, in part due to altered choroid plexus transport activity in the rat. Our findings suggest that CSF dynamics are modulated by the circadian rhythm, rather than merely sleep itself.

Increased CCL-5 (RANTES) Gene Expression in the Choroid Plexus of Dogs with Canine Leishmaniosis

Visceral canine leishmaniasis (CanL) can cause several clinical manifestations, including neurological lesions. Few reports have characterized the lesions observed in the central nervous system (CNS) during CanL; however, its pathogenesis remains unclear. The choroid plexus (CP) is a specialized structure responsible for the production and secretion of cerebrospinal fluid (CSF) and considered an interface between the peripheral immune system and CNS. It can allow the passage of inflammatory cells or pathogens and has the potential to act as a source of inflammatory mediators in several diseases. Thus, this study aimed to evaluate the role of CP as a possible route of inflammatory cells in the development of brain lesions in dogs with CanL, as well as its association with blood–CSF barrier (BCSFB) dysfunction. Samples were collected from 19 dogs that were naturally infected with CanL. We evaluated the histopathological lesions in the brain and investigated the gene expression of the cytokines. Capture enzyme-linked immunosorbent assay (ELISA) was used to evaluate the presence of the same cytokines in the CSF. Biochemical analysis was performed to compare the presence of albumin in the serum and CSF. Indirect ELISA was performed to measure the presence of anti-Leishmania antibodies in the CSF, which would suggest the disruption of the BCSFB. Histopathological evaluation of the dogs’ brains revealed mild-to-severe inflammatory infiltrates, mainly in the CP and meninges. We also detected the presence of anti-Leishmania antibodies and albumin in the CSF, as well as Leishmania DNA in the CP. The gene expression of CCL-5 was increased in the CP of infected dogs compared with that of controls, and there was a tendency for the increase in the gene expression of CXCL-10. Thus, our findings confirm the disfunction of the BCSFB during CanL and suggest that the chemokines CCL-5 and CXCL-10 can be responsible for the recruitment of inflammatory cells found in CP.

Modelling idiopathic intracranial hypertension in rats: contributions of high fat diet and testosterone to intracranial pressure and cerebrospinal fluid production

BackgroundIdiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure (ICP), impaired vision, and headache. Most cases of IIH occur in obese women of childbearing age, though age, BMI, and female sex do not encompass all aspects of IIH pathophysiology. Systemic metabolic dysregulation has been identified in IIH with a profile of androgen excess. However, the mechanistic coupling between obesity/hormonal perturbations and cerebrospinal fluid dynamics remains unresolved.MethodsFemale Wistar rats were either fed a high fat diet (HFD) for 21 weeks or exposed to adjuvant testosterone treatment for 28 days to recapitulate IIH causal drivers. Cerebrospinal fluid (CSF) and blood testosterone levels were determined with mass spectrometry, ICP and CSF dynamics with in vivo experimentation, and the choroid plexus function revealed with transcriptomics and ex vivo isotope-based flux assays.ResultsHFD-fed rats presented with increased ICP (65%), which was accompanied by increased CSF outflow resistance (50%) without altered CSF secretion rate or choroid plexus gene expression. Chronic adjuvant testosterone treatment of lean rats caused elevated ICP (55%) and CSF secretion rate (85%), in association with increased activity of the choroid plexus Na+,K+,2Cl− cotransporter, NKCC1.ConclusionsHFD-induced ICP elevation in experimental rats occurred with decreased CSF drainage capacity. Adjuvant testosterone, mimicking the androgen excess observed in female IIH patients, elevated the CSF secretion rate and thus ICP. Obesity-induced androgen dysregulation may thus contribute to the disease mechanism of IIH.

Increased apparent blood flow and volume of the choroid plexus in the Alzheimer’s Disease patients

BackgroundRecent works suggested the association between the dysfunctional glymphatic system and Alzheimer's Disease, which shows as alternated cerebrospinal fluid production. It is believed that the choroid plexus is the major site of CSF production conventionally and the choroid plexus blood flow is related to the production rate directly. Therefore, we investigated the choroid plexus perfusion in AD patients using arterial spin labeling (ASL) and MRI retrospectively.Method21 AD patients (15 males, 76.1±5.7 years), 36 MCI patients (20 males, 72.6±7.9 years), and 88 healthy controls (40 males, 74.8±8.0 years) from the ADNI3 were included in this study. The lateral choroid plexus regions were segmented automatically based on a 3D U‐net deep learning method, which has been demonstrated with higher accuracy compared to the Freesurfer. In addition, the gray matter mask was segmented from the T1 weighted images using SPM12, and it was used to transfer the ASL and M0 images to the T1 weighted image space. Relative cerebral blood flow was quantified by first dividing the ASL image with its smoothed M0 image (a Gaussian filter with the sigma of 4 pixels), and then normalizing the mean signal of the choroid plexus region with the mean of the gray matter region. The gray matter mask was chosen as the region with a probability higher than 0.5.ResultIn the nonparametric Mann‐Whitney U test, the choroid plexus volume of the AD patients (1.58±0.40ml) was significantly larger (p = 0.036) than that of the healthy controls (1.41±0.39). In addition, the AD patients (0.85±0.30) showed significantly higher (p = 0.017) relative perfusion of the choroid plexus regions than the healthy controls (0.70±0.20).ConclusionThe enlarged volume and increased blood flow of the choroid plexus may suggest the over‐compensation of CSF production in AD patients. However, further investigation is required to separate the blood flow and CSF signal in ASL at the choroid plexus region.

Noninvasive Calculation of Cerebrospinal Fluid Production Using Phase-Contrast Magnetic Resonance Imaging: First Implementation in Augusta, Georgia.

This retrospective review examines the utility of phase-contrast magnetic resonance imaging (PC-MRI) to calculate flow through the aqueduct between the third and fourth ventricles to estimate cerebrospinal fluid (CSF) production. Imaging software quantified the CSF flow rate across the aqueduct of four females and two males at a single center, and the mean of these results was compared to the established mean CSF production calculated by invasive techniques. There was no significant difference between the means, contributing to the body of literature suggesting the utility of PC-MRI in estimating CSF production rates.

Mechanisms of cerebrospinal fluid and brain interstitial fluid production

Fluid homeostasis is fundamental for brain function with cerebral edema and hydrocephalus both being major neurological conditions. Fluid movement from blood into brain is one crucial element in cerebral fluid homeostasis. Traditionally it has been thought to occur primarily at the choroid plexus (CP) as cerebrospinal fluid (CSF) secretion due to polarized distribution of ion transporters at the CP epithelium. However, there are currently controversies as to the importance of the CP in fluid secretion, just how fluid transport occurs at that epithelium versus other sites, as well as the direction of fluid flow in the cerebral ventricles. The purpose of this review is to evaluate evidence on the movement of fluid from blood to CSF at the CP and the cerebral vasculature and how this differs from other tissues, e.g., how ion transport at the blood-brain barrier as well as the CP may drive fluid flow. It also addresses recent promising data on two potential targets for modulating CP fluid secretion, the Na+/K+/Cl− cotransporter, NKCC1, and the non-selective cation channel, transient receptor potential vanilloid 4 (TRPV4). Finally, it raises the issue that fluid secretion from blood is not constant, changing with disease and during the day. The apparent importance of NKCC1 phosphorylation and TRPV4 activity at the CP in determining fluid movement suggests that such secretion may also vary over short time frames. Such dynamic changes in CP (and potentially blood-brain barrier) function may contribute to some of the controversies over its role in brain fluid secretion.

Cerebrospinal Fluid-Basic Concepts Review.

Cerebrospinal fluid plays a crucial role in protecting the central nervous system (CNS) by providing mechanical support, acting as a shock absorber, and transporting nutrients and waste products. It is produced in the ventricles of the brain and circulates through the brain and spinal cord in a continuous flow. In the current review, we presented basic concepts related to cerebrospinal fluid history, cerebrospinal fluid production, circulation, and its main components, the role of the blood-brain barrier and the blood-cerebrospinal fluid barrier in the maintenance of cerebrospinal fluid homeostasis, and the utility of Albumin Quotient (QAlb) evaluation in the diagnosis of CNS diseases. We also discussed the collection of cerebrospinal fluid (type, number of tubes, and volume), time of transport to the laboratory, and storage conditions. Finally, we briefly presented the role of cerebrospinal fluid examination in CNS disease diagnosis of various etiologies and highlighted that research on identifying cerebrospinal fluid biomarkers indicating disease presence or severity, evaluating treatment effectiveness, and enabling understanding of pathogenesis and disease mechanisms is of great importance. Thus, in our opinion, research on cerebrospinal fluid is still necessary for both the improvement of CNS disease management and the discovery of new treatment options.

P12 Patient-specific automated cerebrospinal fluid pressure control to augment spinal wound closure: a case series using LiquoGuard®

Abstract Introduction Post-operative spinal cerebrospinal fluid (CSF) leaks are a common and potentially serious surgical complication. The management of intra- and post-operative leaks is heterogeneous. Numerous studies advocate for dural repair and CSF diversion. The LiquoGuard7 allows automated and precise CSF pressure and volume control, with the calculation of patient-specific biometrics. We sought to summarize our experience with patient-specific CSF automated drainage with layered spinal wound closure. Methods This single-centre case series included patients undergoing complex spinal surgery where: 1) a high-flow intra- and/or postoperative CSF leak was expected and 2) concurrent CSF diversion was performed via lumbar drain attached to a LiquoGuard7®. CSF diversion was tailored to calculated CSF production rates and other case factors to maintain a neutral pressure across the operative site. Results Three patients were included, with a variety of pathologies (T7/T8 disc prolapse; T8-T9; T4-T5 metastatic spinal cord compression). The first two patients underwent CSF diversion to prevent post-op CSF leak, whilst case 3 required this in response to post-op CSF leak. CSF hyperproduction (140-150ml/hr) was evident in all cases. With patient-specific CSF diversion regimes, no cases required further intervention for CSF fistulae repair (including for pleural CSF effusion), wound breakdown or infection. Conclusion Automated patient-specific cerebrospinal fluid drainage may have a role in the closure of complex spinal wounds with high-flow CSF leaks, with a smaller risk profile than traditional manual drainage. Further larger studies are needed to explore the comparative benefits and cost-effectiveness of these devices.

Cerebrospinal Fluid Production and Absorption and Ventricular Enlargement Mechanisms in Hydrocephalus.

Cerebrospinal fluid (CSF) production and absorption concept significantly changed in the early 2010s from "third circulation theory" and "classical bulk flow theory" to a whole new one as follows: First, CSF is mainly produced from interstitial fluid excreted from the brain parenchyma, and CSF produced from the choroid plexus plays an important role in maintaining brain homeostasis. Second, CSF is not absorbed in the venous sinus via the arachnoid granules, but mainly in the dural lymphatic vessels. Finally, the ventricles and subarachnoid spaces have several compensatory direct CSF pathways at the borders attached to the choroid plexus, e.g., the inferior choroidal point of the choroidal fissure, other than the foramina of Luschka and Magendie. In idiopathic normal pressure hydrocephalus (iNPH), the lateral ventricles and basal cistern are enlarged simultaneously due to the compensatory direct CSF pathways. The average total intracranial CSF volume increased from about 150 mL at 20 years to about 350 mL at 70 years due to the decrease in brain volume with aging and further increased above 400 mL in patients with iNPH. CSF movements are composed of a steady microflow produced by the rhythmic wavy movement of motile cilia on the ventricular surface and dynamic pulsatile flow produced by the brain and cerebral artery pulsation, respiration, and head movement. Pulsatile CSF movements might totally decrease with aging, but it in the ventricles might increase at the foramina of Magendie and Luschka dilation. Aging CSF dynamics are strongly associated with ventricular dilatation in iNPH.

Choroid Plexus Enlargement Exacerbates White Matter Hyperintensity Growth through Glymphatic Impairment.

Choroid plexus (CP) is a key regulator in cerebrospinal fluid production, but its contribution to glymphatic clearance function and association with white matter hyperintensity (WMH) remains unclear. This retrospective study included 2 prospective 3.0-T magnetic resonance imaging (MRI) cohorts. In cohort 1, patients with indications for lumbar puncture underwent 3-dimensional T1-weighted sequence (3D-T1) before and at 39 hours after intrathecal administration of contrast agent (glymphatic MRI). In cohort 2, patients with WMH were enrolled from the CIRCLE study and had a median follow-up time of 1.4 years. WMH and CP of the lateral ventricles were automatically segmented on T2 fluid-attenuated inversion recovery (FLAIR) and 3D-T1, respectively. CP volume was expressed as a ratio to intracranial volume. Glymphatic clearance was measured as signal percentage change from baseline to 39 hours at 8 brain locations based on glymphatic MRI in the first cohort, or as noninvasive diffusion tensor image analysis along the perivascular space (DTI-ALPS) index based on DTI in the second cohort. In cohort 1, a total of 52 patients were included. Higher CP volume was correlated with slower glymphatic clearance rate in all brain locations. In cohort 2, a total of 197 patients were included. Baseline CP volume was positively associated with WMH volume and its growth. Furthermore, DTI-ALPS index partially mediated the association of CP with both WMH load and growth. Enlarged CP volume could be an indicator for larger growth of WMH, potentially involving impaired glymphatic clearance function. The exploration of CP may provide a novel perspective to clarify the mechanism of WMH pathogenesis, as well as other glymphatic-related disorders. ANN NEUROL 2023;94:182-195.