Pathophysiology Of Hydrocephalus Research Articles

Ependymal cell lineage reprogramming as a potential therapeutic intervention for hydrocephalus.

Hydrocephalus is a common neurological condition, characterized by the excessive accumulation of cerebrospinal fluid in the cerebral ventricles. Primary treatments for hydrocephalus mainly involve neurosurgical cerebrospinal fluid diversion, which hold high morbidity and failure rates, highlighting the necessity for the discovery of novel therapeutic approaches. Although the pathophysiology of hydrocephalus is highly multifactorial, impaired function of the brain ependymal cells plays a fundamental role in hydrocephalus. Here we show that GemC1 and McIdas, key regulators of multiciliated ependymal cell fate determination, induce direct cellular reprogramming towards ependyma. Our study reveals that ectopic expression of GemC1 and McIdas reprograms cortical astrocytes and programs mouse embryonic stem cells into ependyma. McIdas is sufficient to establish functional activity in the reprogrammed astrocytes. Furthermore, we show that McIdas' expression promotes ependymal cell regeneration in two different postnatal hydrocephalus mouse models: an intracranial hemorrhage and a genetic form of hydrocephalus and ameliorates the cytoarchitecture of the neurogenic niche. Our study provides evidence on the restoration of ependyma in animal models mimicking hydrocephalus that could be exploited towards future therapeutic interventions.

Clinical application of single-shot fast spin-echo sequence for cerebrospinal fluid flow MR imaging.

In normal-pressure hydrocephalus, disturbances in cerebrospinal fluid (CSF) circulation occur; therefore, understanding CSF dynamics is crucial. The two-dimensional phase-contrast (2D-PC) method, a common approach for visualizing CSF flow on MRI, often presents challenges owing to prominent vein signals and excessively high contrast, hindering the interpretation of morphological information. Therefore, we devised a new imaging method that utilizes T2-weighted high-signal intensification of the CSF and saturation pulses, without requiring specialized imaging sequences. This sequence utilized a T2-weighted single-shot fast spin-echo combined with multi-phase imaging synchronized with a pulse wave. Optimal imaging conditions (repetition time, presence/absence of fast recovery, and echo time) were determined using self-made contrast and single-plate phantoms to evaluate signal-to-noise ratio, contrast ratio, and spatial resolution. In certain clinical cases of hydrocephalus, confirming CSF flow using 2D-PC was challenging. However, our method enabled the visualization of CSF flow, proving to be useful in understanding the pathophysiology of hydrocephalus.

Choroid plexus CCL2‒CCR2 signaling orchestrates macrophage recruitment and cerebrospinal fluid hypersecretion in hydrocephalus

The choroid plexus (ChP) serves as the principal origin of cerebrospinal fluid (CSF). CSF hypersecretion due to ChP inflammation has emerged as an important pathogenesis of hydrocephalus recently. Nevertheless, the precise mechanisms of ChP inflammation and the ensuing CSF hypersecretion in hydrocephalus remain ill-defined. In the present study, we elucidate the critical role of macrophages in the pathogenesis of ChP inflammation. Specifically, we identify the chemokine CCL2, released by ChP epithelial cells, recruits CCR2+ monocytes to the ChP thereby inciting hydrocephalus pathogenesis. The accumulated ChP macrophages increase the inflammation in ChP epithelial cells through TNF-α/TNFR1/NF-κB signaling cascade, thereby leading to CSF hypersecretion. Strikingly, augmentation of ChP‒CCL2 using an adeno-associated viral approach (AAV) exacerbates macrophage recruitment, activation, and ventriculomegaly in rat PHH models. Systemic application of Bindarit, a specific CCL2 inhibitor, significantly inhibits ChP macrophage infiltration and activation and reduces CSF secretion rate. Furthermore, the administration of CCR2 antagonist (INCB 3284) reduces ChP macrophage accumulation and ventriculomegaly. This study not only unveils the ChP CCL2‒CCR2 signaling in the pathophysiology of hydrocephalus but also unveils Bindarit as a promising therapeutic choice for the management of posthemorrhagic hydrocephalus.

Understanding and Modeling the Pathophysiology of Hydrocephalus: In Search of Better Treatment Options

Hydrocephalus is caused by an overproduction of cerebrospinal fluid (CSF), an obstruction of fluid movement, or improper reabsorption. CSF accumulation in the brain’s ventricles causes ventriculomegaly, increased intracranial pressure, inflammation, and neural cell injury. Hydrocephalus can arise from brain trauma, hemorrhage, infection, tumors, or genetic mutations. Currently, there is no cure for hydrocephalus. Treatments like shunting and endoscopic third ventriculostomies are used, but, unfortunately, these therapeutic approaches require brain surgery and have high failure rates. The choroid plexus epithelium (CPe) is thought to be the major producer of CSF in the brain. It is a polarized epithelium that regulates ion and water movement from a fenestrated capillary exudate to the ventricles. Despite decades of research, control of electrolyte movement in the CPe is still not fully understood. This review discusses important transporters on the CPe, how some of these are regulated, and which of them could be potential targets for hydrocephalus treatment. To advance the development of hydrocephalus treatments, physiologically relevant preclinical models are crucial. This review covers some of the current animal and cell culture methods used to study hydrocephalus and highlights the need to develop standardized preclinical models that are used by multiple investigators in order to replicate critical findings and resolve controversies regarding potential drug targets.

Development of shunt valves used for treating hydrocephalus: comparison with endoscopy treatment.

The pathophysiology of hydrocephalus is not clearly defined. Thus, treatment will remain empirical until a fuller understanding of the various forms of hydrocephalus is achieved. Valve-controlled shunting has been the mainstay of therapy since the late 1950s. Initially, shunting occurred from the ventricular system to the atrium. In the 1970s, VA shunts were replaced by ventriculoperitoneal shunts as the primary location for the distal end. Multiple types of one-way valve systems have been developed in the pursuit of draining the appropriate amount of CSF that avoids either overdrainage or underdrainage while preserving normal brain development and cognition. These valves are reviewed and compared as to their function. Other locations for the distal end of the shunting system are reviewed to include pleural space and gallbladder. The lumbar subarachnoid space as the proximal location for a shunt is also reviewed. The only other surgical alternative for treating hydrocephalus is endoscopic third ventriculostomy. Since 2000, approximately 50% of children with hydrocephalus have been shown to be candidates for ETV. The benefits are the lack of need for an artificial shunt system and thus lower rates of infection and over time fewer reoperations. Future progress is dependent on improved shunt valve systems that are affordable worldwide and ready availability of ETV in developing countries. Anatomic and molecular causes of hydrocephalus need to be defined so that medications or genetic modifications become available for potential cure of hydrocephalus.

Changes in TRPV4, AQP1, and AQP4 in a Genetic Model of Hydrocephalus Treated with a TRPV4 Antagonist

Hydrocephalus occurs as a result of cerebrospinal fluid (CSF) accumulating in the brain’s ventricles causing ventriculomegaly. Hydrocephalus can affect various cell types in the brain, and this study focuses on choroid plexus epithelial cells (CPe) and astrocytes. The choroid plexus is a tight epithelial structure within the ventricular system, responsible for producing CSF. Astrocytes are supportive cells that serve in blood‐brain barrier maintenance and brain fluid/electrolyte regulation. The CP and astrocytes contain channels and transporters that are important in regulating both CSF and brain interstitial fluid. These include transient receptor potential vanilloid 4 (TRPV4), aquaporin 1 (AQP1), and aquaporin 4 (AQP4). TRPV4 is a mechanosensitive channel and has been implicated in osmotic regulation. AQPs are a family of membrane proteins that facilitate water transport in various tissues. The CPe expresses AQP1 and TRPV4 which may be important in CSF production. Astrocytes express TRPV4 and AQP4 on their endfeet to regulate cell volume and vascular permeability. Previous studies done by the Blazer‐Yost laboratory have shown increases in AQP1, but not TRPV4 mRNA of CPe from hydrocephalic animals compared to wildtype. This study further examined changes in localization and expression of TRPV4, AQP1, and AQP4 in a rodent model of hydrocephalus.A single missense point mutation in the Transmembrane 67 (TMEM67) protein, that causes a ciliopathy resulting in hydrocephalus and polycystic kidney disease (PKD) in our rodent model, is orthologous to the human Meckel Gruber syndrome type 3 (MKS3). Treatment with the TRPV4 antagonist, RN1734, ameliorates hydrocephalus in our genetic model of hydrocephalus. Using immunohistochemical techniques, TRPV4, AQP1, and AQP4 antibodies were used to examine localization in untreated and RN1734 treated hydrocephalic animals at P15. Changes of AQP4 and TRPV4 were observed in the subventricular zone of homozygous animals. RTqPCR was used to quantitate mRNA from the CPe and subventricular region of the cortex. Preliminary RTqPCR showed increased AQP1, decreased TRPV4 and no change in AQP4 mRNA in the cortex and CPe of P15 untreated and RN1734 treated hydrocephalic animals compared to wild‐type. These data suggests that the changes occurring may be posttranslational. To observe this, Western blots were utilized to look at changes in protein. The protein expression of AQP1 and AQP4 may be increased in untreated cortical tissue from hydrocephalic animals, while total TRPV4 remaining unchanged. AQP1 and AQP4 may be still increased, while total TRPV4 decreased in animals treated with RN1734. These results provide further characterization of the role of several channels and transporters in the pathophysiology of hydrocephalus. Future studies will explore post‐translational changes in protein expression and membrane localization to compliment these studies. Examining channels and transporters can elucidate how brain fluid regulation may be altered in hydrocephalus and produce targets for pharmacological treatment in the future.

AQP4 labels a subpopulation of white matter-dependent glial radial cells affected by pediatric hydrocephalus, and its expression increased in glial microvesicles released to the cerebrospinal fluid in obstructive hydrocephalus

Hydrocephalus is a distension of the ventricular system associated with ventricular zone disruption, reactive astrogliosis, periventricular white matter ischemia, axonal impairment, and corpus callosum alterations. The condition's etiology is typically attributed to a malfunction in classical cerebrospinal fluid (CSF) bulk flow; however, this approach does not consider the unique physiology of CSF in fetal and perinatal patients. The parenchymal fluid contributes to the glymphatic system, and plays a fundamental role in pediatric hydrocephalus, with aquaporin 4 (AQP4) as the primary facilitator of these fluid movements. Despite the importance of AQP4 in the pathophysiology of hydrocephalus, it’s expression in human fetal life is not well-studied. This manuscript systematically defines the brain expression of AQP4 in human brain development under control (n = 13) and hydrocephalic conditions (n = 3). Brains from 8 postconceptional weeks (PCW) onward and perinatal CSF from control (n = 2), obstructive (n = 6) and communicating (n = 6) hydrocephalic samples were analyzed through immunohistochemistry, immunofluorescence, western blot, and flow cytometry. Our results indicate that AQP4 expression is observed first in the archicortex, followed by the ganglionic eminences and then the neocortex. In the neocortex, it is initially at the perisylvian regions, and lastly at the occipital and prefrontal zones. Characteristic astrocyte end-feet labeling surrounding the vascular system was not established until 25 PCW. We also found AQP4 expression in a subpopulation of glial radial cells with processes that do not progress radially but, rather, curve following white matter tracts (corpus callosum and fornix), which were considered as glial stem cells (GSC). Under hydrocephalic conditions, GSC adjacent to characteristic ventricular zone disruption showed signs of early differentiation into astrocytes which may affect normal gliogenesis and contribute to the white matter dysgenesis. Finally, we found that AQP4 is expressed in the microvesicle fraction (p < 0.01) of CSF from patients with obstructive hydrocephalus. These findings suggest the potential use of AQP4 as a diagnostic and prognostic marker of pediatric hydrocephalus and as gliogenesis biomarker.

A novel model of acquired hydrocephalus for evaluation of neurosurgical treatments

BackgroundMany animal models have been used to study the pathophysiology of hydrocephalus; most of these have been rodent models whose lissencephalic cerebral cortex may not respond to ventriculomegaly in the same way as gyrencephalic species and whose size is not amenable to evaluation of clinically relevant neurosurgical treatments. Fewer models of hydrocephalus in gyrencephalic species have been used; thus, we have expanded upon a porcine model of hydrocephalus in juvenile pigs and used it to explore surgical treatment methods.MethodsAcquired hydrocephalus was induced in 33–41-day old pigs by percutaneous intracisternal injections of kaolin (n = 17). Controls consisted of sham saline-injected (n = 6) and intact (n = 4) animals. Magnetic resonance imaging (MRI) was employed to evaluate ventriculomegaly at 11–42 days post-kaolin and to plan the surgical implantation of ventriculoperitoneal shunts at 14–38-days post-kaolin. Behavioral and neurological status were assessed.ResultsBilateral ventriculomegaly occurred post-induction in all regions of the cerebral ventricles, with prominent CSF flow voids in the third ventricle, foramina of Monro, and cerebral aqueduct. Kaolin deposits formed a solid cast in the basal cisterns but the cisterna magna was patent. In 17 untreated hydrocephalic animals. Mean total ventricular volume was 8898 ± 5917 SD mm3 at 11–43 days of age, which was significantly larger than the baseline values of 2251 ± 194 SD mm3 for 6 sham controls aged 45–55 days, (p < 0.001). Past the post-induction recovery period, untreated pigs were asymptomatic despite exhibiting mild-moderate ventriculomegaly. Three out of 4 shunted animals showed a reduction in ventricular volume after 20–30 days of treatment, however some developed ataxia and lethargy, from putative shunt malfunction.ConclusionsKaolin induction of acquired hydrocephalus in juvenile pigs produced an in vivo model that is highly translational, allowing systematic studies of the pathophysiology and clinical treatment of hydrocephalus.

Relationship Between Oxidative Stress, Tau Level and Antioxidant Mechanisms of the KEAP-1/NRF-2/HO-1 in Children with Hydrocephalus.

Hydrocephalus is a complex neurologic disorder that has a widespread impact on the central nervous system and a multifactor disease which affects the CSF dynamics and causes severe neurological impairments in children. The pathophysiology of hydrocephalus is not fully understood. However, increasing evidence suggests that oxidative stress may be an important factor in the pathogenesis of hydrocephalus. The purpose of this study is to investigate the relationship of the KEAP-1/NRF-2/HO-1 pathway, one of the main regulators of the antioxidant system in the hydrocephalus pathology, on oxidative stress and tau protein level. The study included 32 patients with hydrocephalus and 32 healthy controls. KEAP-1, NRF-2, HO-1, TAU, and MPO levels are measured using ELISA method TAS, TOS, and Total THIOL colorimetric method. KEAP-1, TAS, and Total THIOL levels were found significantly lowerer in the hydrocephalus group than in the control group. Nevertheless, it was identified that in the hydrocephalus group that the NRF-2, HO-1, TAU, MPO, TOS, and OSI levels were significantly elevated. In conclusion, although the KEAP-1/NRF-2/HO-1 pathway is activated in patients with hydrocephalus, it is identified that the antioxidant defense system is insufficient and ultimately leads to elevated oxidative stress. The elevation in the tau level may be an indicator of oxidative stress induced neurodegenerative damage.

Integrated understanding of hydrocephalus \u2014 a practical approach for a complex disease

Most of childhood hydrocephalus are originating during infancy. It is considered to be a complex disease since it is developed on the basis of heterogeneous pathophysiological mechanisms and different pathological conditions as well as during different age groups. Hence, it is of relevant importance to have a practical concept in mind, how to categorize hydrocephalus to surgically better approach this disease. The current review should offer further basis of discussion on a disease still most frequently seen in Pediatric Neurosurgery. Current literature on pathophysiology and classification of pediatric hydrocephalus has been reviewed to integrate the different published concepts of hydrocephalus for pediatric neurosurgeons. The current understanding of infant and childhood hydrocephalus pathophysiology is summarized. A simplified concept based on seven factors of CSF dynamics is elaborated and discussed in the context of recent discussions. The seven factors such as pulsatility, CSF production, major CSF pathways, minor CSF pathways, CSF absorption, venous outflow, and respiration may have different relevance and may also overlap for the individual hydrocephalic condition. The surgical options available for pediatric neurosurgeons to approach hydrocephalus must be adapted to the individual condition. The heterogeneity of hydrocephalus causes mostly developing during infancy warrant a simplified overview and understanding for an everyday approach. The proposed guide may be a basis for further discussion and may serve for a more or less simple categorization to better approach hydrocephalus as a pathophysiological complex disease.

Multi-omic analysis elucidates the genetic basis of hydrocephalus.

SUMMARYWe conducted PrediXcan analysis of hydrocephalus risk in ten neurological tissues and whole blood. Decreased expression of MAEL in the brain was significantly associated (Bonferroni-adjusted p < 0.05) with hydrocephalus. PrediXcan analysis of brain imaging and genomics data in the independent UK Biobank (N = 8,428) revealed that MAEL expression in the frontal cortex is associated with white matter and total brain volumes. Among the top differentially expressed genes in brain, we observed a significant enrichment for gene-level associations with these structural phenotypes, suggesting an effect on disease risk through regulation of brain structure and integrity. We found additional support for these genes through analysis of the choroid plexus transcriptome of a murine model of hydrocephalus. Finally, differential protein expression analysis in patient cerebrospinal fluid recapitulated disease-associated expression changes in neurological tissues, but not in whole blood. Our findings provide convergent evidence highlighting the importance of tissue-specific pathways and mechanisms in the pathophysiology of hydrocephalus.

Changes in TRPV4, AQP1, and AQP4 in a Genetic Model of Hydrocephalus

Hydrocephalus has an incidence of 1:1000 in the pediatric population. In hydrocephalus, cerebrospinal fluid (CSF) accumulates in the brain's ventricles causing ventriculomegaly. Hydrocephalus can affect various cell types in the brain, and this study focuses on astrocytes and choroid plexus epithelial cells (CPe). The choroid plexus is a tight epithelial structure within the ventricular system, responsible for producing CSF. Astrocytes are supportive cells that serve in blood-brain barrier maintenance and brain fluid/electrolyte regulation. The CP and astrocytes contain channels and transporters that are important in regulating both CSF and brain interstitial fluid. These include transient receptor potential vanilloid 4 (TRPV4), aquaporin 1 (AQP1), and aquaporin 4 (AQP4). TRPV4 is a mechanosensitive channel and has been implicated in osmotic regulation. AQPs are a family of membrane proteins that facilitate water transport in various tissues. The CPe expresses AQP1 and TRPV4 which may be important in CSF production. Astrocytes express TRPV4 and AQP4 on their endfeet to regulate cell volume and vascular permeability. Previous studies done by the Blazer-Yost laboratory have shown increases in AQP1, but not TRPV4 mRNA of CPe from hydrocephalic animals compared to wildtype. This study further examined changes in localization and expression of TRPV4, AQP1, and AQP4 in a rodent model of hydrocephalus. A single missense point mutation in the Transmembrane 67 (TMEM67) protein causes a ciliopathy resulting in hydrocephalus and polycystic kidney disease (PKD) in our rodent model. This mutation is orthologous to the human Meckel Gruber syndrome type 3 (MKS3). The TMEM67 gene codes for Mecklin, a ciliary protein found predominately in the brain and kidneys. The phenotypes seen in TMEM67 (-/-) (homozygous) animals are so severe that death will occur by post-natal day 21 (P21). We have previously shown that treatment with TRPV4 antagonists ameliorate hydrocephalus in our genetic model of hydrocephalus. Using immunohistochemical techniques, TRPV4, AQP1, and AQP4 antibodies were used to examine localization in hydrocephalic animals at P15. Changes of AQP4 and TRPV4 were observed in the cortex of homozygous animals. AQP4 appears to move from astrocyte endfeet in hydrocephalic animals and is increased at the brain-CSF barrier. TRPV4 appears to be increased throughout the cortex. qPCR was used to quantitate mRNA from the CPe and cortex. Preliminary qPCR showed increased TRPV4, AQP1, and AQP4 mRNA in the cortex and CPe of P15 hydrocephalic animals compared to wild-type. In summary, in a model of hydrocephalus, channels and transporters show changes in localization and transcription. These results provide further characterization of the role of several channels and transporters in the pathophysiology of hydrocephalus. Futures studies will explore developmental changes in protein expression and membrane localization to compliment these studies. Examining channels and transporters can elucidate how brain fluid regulation may be altered in hydrocephalus and produce targets for pharmacological treatment in the future.

Role of aquaporins in hydrocephalus: what do we know and where do we stand? A systematic review.

Glymphatic fluid circulation may be considered the lymphatic system of the brain and the main role of such system seems to be played by aquaporins (AQPs), a family of proteins which regulates water exchange, in particular AQP4 and 1. Alterations of glymphatic fluid circulation through AQPs variations are now emerging as central elements in the pathophysiology of different brain conditions, like hydrocephalus. This systematic review provides an insight about the role of AQPs in hydrocephalus establishment and compensation, investigating their possible role as diagnostic tools or therapeutic targets. PubMed database was screened searching for the relevant existing literature in English language published until February 29th 2020, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. A total of 40 articles met the inclusion criteria for our systematic analysis. AQP4 resulted the most studied water channel, followed by AQP1. The changes in cerebrospinal fluid (CSF), brain parenchyma and choroid plexus (CP) in different hydrocephalus type were analyzed. Moreover, important pharmacological interactions regarding AQP and molecules or conditions were discussed. A very interesting result is the general consensus on increase of AQP4 in hydrocephalic patients, unless in patients suffering from idiopathic normal pressure hydrocephalus, where AQP4 shows a tendency in reduction. AQP seem to play a central role in the pathophysiology of hydrocephalus and in its compensation mechanisms. Further studies are required to definitively establish their precise roles and their quantitative changes to allow their utilization as diagnostic tools or therapeutic targets.

Magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamics in idiopathic normal pressure hydrocephalus.

Disturbed clearance of toxic metabolites from the brain via cerebrospinal fluid is emerging as an important mechanism behind dementia and neurodegeneration. To this end, magnetic resonance imaging work-up of dementia diseases is largely focused on anatomical derangements of the brain. This study explores magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamics in patients with the dementia subtype idiopathic normal pressure hydrocephalus and a cohort of reference subjects. All study participants underwent multi-phase magnetic resonance imaging up to 48 h after intrathecal administration of the contrast agent gadobutrol (0.5 ml, 1 mmol/ml), serving as cerebrospinal fluid tracer. Imaging biomarkers of cerebrospinal fluid tracer dynamics (i.e. ventricular reflux grades 0–4 and clearance) were compared with anatomical magnetic resonance imaging biomarkers of cerebrospinal fluid space anatomy (Evans’ index, callosal angle and disproportional enlargement of subarachnoid spaces hydrocephalus) and neurodegeneration (Schelten’s medial temporal atrophy scores, Fazeka’s scores and entorhinal cortex thickness). The imaging scores were also related to a pulsatile intracranial pressure score indicative of intracranial compliance. In shunt-responsive idiopathic normal pressure hydrocephalus, the imaging biomarkers demonstrated significantly altered cerebrospinal fluid tracer dynamics (ventricular reflux grades 3–4 and reduced clearance of tracer), deranged cerebrospinal fluid space anatomy and pronounced neurodegeneration. The altered MRI biomarkers were accompanied by pressure indices of impaired intracranial compliance. In conclusion, we present novel magnetic resonance imaging biomarkers characterizing idiopathic normal pressure hydrocephalus pathophysiology, namely measures of cerebrospinal fluid molecular redistribution and clearance, which add information to traditional imaging scores of cerebrospinal fluid space anatomy and neurodegeneration.

Intraventricular Hemorrhage Induces Rapid Calcium Signaling and Transcriptional Changes in the Developing Choroid Plexus

Abstract INTRODUCTION Intraventricular hemorrhage (IVH) leads to acute hydrocephalus in a subset of preterm infants by unclear mechanisms that potentially include increased cerebrospinal fluid (CSF) production by the choroid plexus (ChP), based on recent work in adult rats (Karimy et al., 2017). The earliest physiologic changes in ChP epithelial cells likely involve calcium signaling, which is a known cellular messenger in other secretory epithelial cell populations. The following experiments utilize rapid calcium imaging to evaluate how calcium signaling is regulated in embryonic ChP explants, and additionally determine specific transcriptional alterations in Vivo. METHODS 1) Calcium imaging of embryonic explants: Lateral ventricle ChP is dissected at embryonic day 14.5 (E14.5) from a conditional transgenic mouse line (FoxJ1-Cre; Gcamp6f). The ChP explants are kept viable with artificial CSF, exposed to focal blood injections, and imaged for calcium responses using epifluorescence and two-photon imaging. 2) Transcriptional analysis in a model of preterm IVH: Quantitative RT-PCR is performed on acutely dissected ChP at 24 and 48 hr, following in utero injection of age-matched blood in the lateral ventricles of individual embryos (E14.5 pregnant CD1 mice). RESULTS Upon exposure to age-matched E14.5 plasma, nearly all ChP epithelial cells rapidly release highly concentrated intracellular calcium followed by a mosaic pattern of recurrent calcium release. Using different conditions of calcium blockade, we identify endoplasmic reticulum storage as the primary source of intracellular calcium release. Expression of NKCC1 (the predominant apical ion co-transporter in the ChP) rises by 24 hr, suggesting increased ChP ion permeability, consistent with prior reports of a CSF hypersecretion phenotype. CONCLUSION IVH causes immediate intracellular calcium release by the ChP epithelia, followed by increased NKCC1 transcription within 24 hr. Together, these data suggest a rapid and dynamic embryonic ChP responsiveness to hemorrhage and contributes to our understanding of IVH-induced hydrocephalus pathophysiology.

Comprehensive analysis of differentially expressed profiles of long non-coding RNAs and messenger RNAs in kaolin-induced hydrocephalus

BackgroundsThe pathophysiology of hydrocephalus induced brain damage remains unclear. Long non-coding RNAs (lncRNAs) have been demonstrated to be implicated in many central nervous system diseases. However, the roles of lncRNAs in hydrocephalus injury are poorly understood. MethodsThe present study depicted the expression profiles of lncRNAs and messenger RNAs (mRNAs) in C57BL/6 mice with kaolin-induced hydrocephalus and saline controls using high-throughput RNA sequencing. Afterward, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify potential targets that correlated with hydrocephalus. In addition, co-expression networks and cis- and trans-regulation were predicted using bioinformatics methods. Finally, representative lncRNAs and mRNAs were further validation using quantitative real-time polymerase chain reaction. ResultsA total of 1575 lncRNAs and 1168 mRNAs were differentially expressed (DE) in hydrocephalus. GO and KEGG analyses indicated several immune and inflammatory response-associated pathways may be important in the hydrocephalus. Besides, functional enrichment analysis based on co-expression network showed several similar pathways, such as chemokine signaling pathway, phagosome, MAPK signaling pathway and complement and coagulation cascade. Cis-regulation prediction revealed 5 novel lncRNAs might regulate their nearby coding genes, and trans-regulation revealed several lncRNAs participate in pathways regulated by transcription factors, including BPTF, FOXM1, NR5A2, P2RX5, and NR6A1. ConclusionsIn conclusion, our results provide candidate genes involved in hydrocephalus and suggest a new perspective on the modulation of lncRNAs in hydrocephalus.

Posthemorrhagic hydrocephalus development after germinal matrix hemorrhage: Established mechanisms and proposed pathways

In addition to being the leading cause of morbidity and mortality in premature infants, germinal matrix hemorrhage (GMH) is also the leading cause of acquired infantile hydrocephalus. The pathophysiology of posthemorrhagic hydrocephalus (PHH) development after GMH is complex and vaguely understood, although evidence suggests fibrosis and gliosis in the periventricular and subarachnoid spaces disrupts normal cerebrospinal fluid (CSF) dynamics. Theories explaining general hydrocephalus etiology have substantially evolved from the original bulk flow theory developed by Dr. Dandy over a century ago. Current clinical and experimental evidence supports a new hydrodynamic theory for hydrocephalus development involving redistribution of vascular pulsations and disruption of Starling forces in the brain microcirculation. In this review, we discuss CSF flow dynamics, history and development of theoretical hydrocephalus pathophysiology, and GMH epidemiology and etiology as it relates to PHH development. We highlight known mechanisms and propose new avenues that will further elucidate GMH pathophysiology, specifically related to hydrocephalus.

Long-term Zika complications

Congenital Zika Syndrome (CZS) has as a main characteristic the brain impairment, with microcephalus, however it is still little known about this entity and its clinical spectrum that includes newborns with normal head circumference. In addition to congenital microcephaly and craniofacial disproportion, a range of manifestations have been associated with CZS, including neurologic symptoms, arthrogryposis, hearing and ocular abnormalities. The neurologic findings of severe affected patients include irritability, hyperexcitability, hypertonia and dysphagia. Regardless of the ophthalmologic impairment, more than a half of the patients with the CZS and severe microcephaly have presented poor interaction with the environment related to cortical impairment. Epilepsy is frequent, even in patients with normal head circumference at birth. The arthrogrypotic joints did not result from abnormalities of the joints themselves and are likely to be of neurogenic origin. The pattern of brain images abnormalities in CZS has been fully described. The pattern of calcifications at the junction between cortical and subcortical white matter, in addition to the cortical developmental disorders predominantly on frontal regions confers highly suggestive pattern of CZS. Cerebellar atrophy and malformations of the brainstem may also occur. Unlike other congenital infections, several patients are developing hydrocephalus between 3 to 18 months. The pathophysiology of hydrocephalus in CZS is still unknown The complete neurological picture requires the central nervous system maturation and it will only become clear after, at least 18 months, so to a better definition of congenital Zika syndrome we need a longer follow-up.

Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus.

IntroductionHydrocephalus is a complex neurological disorder with a pervasive impact on the central nervous system. Previous work has demonstrated derangements in the biochemical profile of cerebrospinal fluid (CSF) in hydrocephalus, particularly in infants and children, in whom neurodevelopment is progressing in parallel with concomitant neurological injury. The objective of this study was to examine the CSF of children with congenital hydrocephalus (CHC) to gain insight into the pathophysiology of hydrocephalus and identify candidate biomarkers of CHC with potential diagnostic and therapeutic value.MethodsCSF levels of amyloid precursor protein (APP) and derivative isoforms (sAPPα, sAPPβ, Aβ42), tau, phosphorylated tau (pTau), L1CAM, NCAM-1, aquaporin 4 (AQP4), and total protein (TP) were measured by ELISA in 20 children with CHC. Two comparative groups were included: age-matched controls and children with other neurological diseases. Demographic parameters, ventricular frontal-occipital horn ratio, associated brain malformations, genetic alterations, and surgical treatments were recorded. Logistic regression analysis and receiver operating characteristic curves were used to examine the association of each CSF protein with CHC.ResultsCSF levels of APP, sAPPα, sAPPβ, Aβ42, tau, pTau, L1CAM, and NCAM-1 but not AQP4 or TP were increased in untreated CHC. CSF TP and normalized L1CAM levels were associated with FOR in CHC subjects, while normalized CSF tau levels were associated with FOR in control subjects. Predictive ability for CHC was strongest for sAPPα, especially in subjects ≤12 months of age (p<0.0001 and AUC = 0.99), followed by normalized sAPPβ (p = 0.0001, AUC = 0.95), tau, APP, and L1CAM. Among subjects ≤12 months, a normalized CSF sAPPα cut-point of 0.41 provided the best prediction of CHC (odds ratio = 528, sensitivity = 0.94, specificity = 0.97); these infants were 32 times more likely to have CHC.ConclusionsCSF proteins such as sAPPα and related proteins hold promise as biomarkers of CHC in infants and young children, and provide insight into the pathophysiology of CHC during this critical period in neurodevelopment.

Aquaporin Water Channels and Hydrocephalus

The aquaporins (AQPs) are a family of water-transporting proteins that are broadly expressed in mammalian cells. Two AQPs in the central nervous system, AQP1 and AQP4, might play a role in hydrocephalus and are thus potential drug targets. AQP1 is expressed in the ventricular-facing membrane of choroid plexus epithelial cells, where it facilitates the secretion of cerebrospinal fluid (CSF). AQP4 is expressed in astrocyte foot processes and ependymal cells lining ventricles, where it appears to facilitate the transport of excess water out of the brain. Altered expression of these AQPs in experimental animal models of hydrocephalus and limited human specimens suggests their involvement in the pathophysiology of hydrocephalus, as do data in knockout mice demonstrating a protective effect of AQP1 deletion and a deleterious effect of AQP4 deletion in hydrocephalus. Though significant questions remain, including the precise contribution of AQP1 to CSF secretion in humans and the mechanisms by which AQP4 facilitates clearance of excess brain water, AQP1 and AQP4 have been proposed as potential drug targets to reduce ventricular enlargement in hydrocephalus.