Accumulation Of Cerebrospinal Fluid Research Articles

Patients of idiopathic normal-pressure hydrocephalus have small dural sac in cervical and upper thoracic levels: A supposed causal association.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder presenting a triad including dementia and ventricular enlargement. The mechanism causing excessive cerebrospinal fluid (CSF) accumulation in the ventricles in iNPH is poorly understood. We hypothesized that the age-related degradation of the spinal shock-absorbing system composed of a spinal dural sac (SDS) and surrounding soft tissue, preventing ventricular enlargement caused by wide CSF pulsation driven by heartbeats, may be involved in the ventricular enlargement observed in iNPH. Sixty-four patients with iNPH in their seventies who underwent a lumboperitoneal shunt and a control group of 79 people in the same age group who underwent brain check-ups were included in the study. We compared the sizes of the cervical and upper parts of the thoracic SDS using magnetic resonance imaging between the two groups. The anterior-posterior distances of the dural sac at C5 were shorter in patients with iNPH of both sexes than those in the control group (P = 0.0008 in men and P = 0.0047 in women). The number of disc levels with disappeared CSF space surrounding the cervical cord was more in iNPH (P = 0.0176 and P = 0.0003). The midsagittal area of the upper part of the spinal sac, C2-Th4, was smaller in iNPH (P = 0.0057 and P = 0.0290). Narrowing of the cervical dural sac and midsagittal area in the upper part of the SDS in patients with iNPH may reflect the degradation of the shock-absorbing mechanism for CSF pressure pulsations, which may cause iNPH or at least aggravate iNPH by other unknown causes.

Cerebral microvascular markers of intracranial pressure in acute and subacute porcine hydrocephalus model

Hydrocephalus affects 1.1% of infants, resulting in abnormal accumulation of cerebrospinal fluid and elevated intracranial pressure (ICP). Elevated ICP can occur prior to detectable morphological changes using computed tomography, resulting in delayed diagnosis and treatment. To improve early diagnosis, we propose vascular imaging using ultrasound localization microscopy (ULM) and ultrafast Doppler to measure cerebral blood flow changes due to acute to subacute elevations in ICP. We performed a pre-clinical study on a neonatal porcine model with 30 min, 8 h, 12 h, and 24 h ICP elevations while performing brain ultrasound measurements in hourly intervals. Ultrafast plane-wave ultrasound imaging was implemented using the Verasonics Vantage-256 and GE IC59D curved array probe at 400Hz frame rate. Lumason contrast agent was infused into each animal, providing tracers for ULM and enhancing the ultrafast Doppler imaging. Based on preliminary analysis, ultrafast Doppler showed reduced total cerebral blood volume after acute ICP elevation. ULM showed highly correlated parabolic reductions in cortical microcirculation with increasing ICP. Drastic reductions in cerebral microcirculation but less so in microcirculation accompanied microdialysis evidence of brain ischemia. Additionally, there were spatiotemporal changes in cerebral microvascular flow with varying ICP durations that warrant additional investigations using ultrafast ultrasound imaging.

The miRNA transcriptome of cerebrospinal fluid in preterm infants reveals the signaling pathways that promote reactive gliosis following cerebral hemorrhage.

Germinal Matrix-Intraventricular Haemorrhage (GM-IVH) is one of the most common neurological complications in preterm infants, which can lead to accumulation of cerebrospinal fluid (CSF) and is a major cause of severe neurodevelopmental impairment in preterm infants. However, the pathophysiological mechanisms triggered by GM-IVH are poorly understood. Analyzing the CSF that accumulates following IVH may allow the molecular signaling and intracellular communication that contributes to pathogenesis to be elucidated. Growing evidence suggests that miRs, due to their key role in gene expression, have a significant utility as new therapeutics and biomarkers. The levels of 2,083 microRNAs (miRs) in 15 CSF samples from 10 infants with IVH were measured using miRNA whole transcriptome sequencing. Gene ontology (GO) and miR family analysis were used to uncover dysregulated signalling which were then validated in vitro in human foetal neural progenitor cells treated with IVH-CSF. Five hundred eighty-seven miRs were differentially expressed in the CSF extracted at least 2 months after injury, compared to CSF extracted within the first month of injury. GO uncovered key pathways targeted by differentially expressed miRs including the MAPK cascade and the JAK/STAT pathway. Astrogliosis is known to occur in preterm infants, and we hypothesized that this could be due to abnormal CSF-miR signaling resulting in dysregulation of the JAK/STAT pathway - a key controller of astrocyte differentiation. We then confirmed that treatment with IVH-CSF promotes astrocyte differentiation from human fetal NPCs and that this effect could be prevented by JAK/STAT inhibition. Taken together, our results provide novel insights into the CSF/NPCs crosstalk following perinatal brain injury and reveal novel targets to improve neurodevelopmental outcomes in preterm infants.

An Overview of Hydrocephalus and Shunts Used in The Clinical Management of Hydrocephalus

Hydrocephalus is a complex neurological condition characterized by an abnormal accumulation of cerebrospinal fluid (CSF) within the ventricles of the brain, leading to increased intracranial pressure. The clinical management of hydrocephalus often involves the surgical placement of a shunt system to divert CSF and restore normal fluid dynamics. This article provides a comprehensive overview of hydrocephalus, its etiology, clinical presentation, and various types of shunts used in its management. The outline of this report encompasses the principles of shunt surgery, indications for shunt placement and primary types of shunts used in the clinical management of hydrocephalus, including ventriculoperitoneal (VP), ventriculoatrial (VA), ventriculopleural (VPL), lumboperitoneal (LP) and ventriculo-subgaleal (VS) shunts. Additionally, some non-conventional shunts such as ventriculo-osseous, ventriculo renal, ventriculo gall bladder, intraventricular (Aqueductal stents) and long-tunnelled external ventricular drains are also discussed. The distinct features of each shunt type, its associated advantages, limitations and complications are also outlined together with a comparison between pressure vs flow regulated valves. An understanding of the different shunt types and their specific characteristics is essential for clinicians to make informed decisions in tailoring treatment to individual patients. This review offers a comprehensive understanding of shunt characteristics which we believe will empower clinicians to make informed decisions tailored to individual patients, ensuring effective CSF diversion and long-term management of hydrocephalus.

Pathogenic role of autoantibodies at the ependyma in autoimmune disorders of the central nervous system.

Ependymal cells make up the epithelial monolayer that lines the brain ventricles and the spinal cord central canal that are filled with cerebrospinal fluid. The ependyma has several functions, including regulating solute exchange between the cerebrospinal fluid and parenchyma, controlling microcirculation of cerebrospinal fluid via coordinated ciliary beating, and acting as a partial barrier. Dysregulation of these functions can lead to waste clearance impairment, cerebrospinal fluid accumulation, hydrocephalus, and more. A role for ependymal cells in a variety of neurological disorders has been proposed, including in neuromyelitis optica and multiple sclerosis, two autoimmune demyelinating diseases of the central nervous system, where periventricular damage is common. What is not known is the mechanisms behind how ependymal cells become dysregulated in these diseases. In neuromyelitis optica, it is well established that autoantibodies directed against Aquaporin-4 are drivers of disease, and it has been shown recently that these autoantibodies can drive ependymal cell dysregulation. We propose a similar mechanism is at play in multiple sclerosis, where autoantibodies targeting a glial cell protein called GlialCAM on ependymal cells are contributing to disease. GlialCAM shares high molecular similarities with the Epstein-Barr virus (EBV) protein EBNA1. EBV has recently been shown to be necessary for multiple sclerosis initiation, yet how EBV mediates pathogenesis, especially in the periventricular area, remains elusive. In this perspective article, we discuss how ependymal cells could be targeted by antibody-related autoimmune mechanisms in autoimmune demyelinating diseases and how this is implicated in ventricular/periventricular pathology.

Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models

BackgroundHydrocephalus is a pathological accumulation of cerebrospinal fluid (CSF), leading to ventriculomegaly. Hydrocephalus may be primary or secondary to traumatic brain injury, infection, or intracranial hemorrhage. Regardless of cause, current treatment involves surgery to drain the excess CSF. Importantly, there are no long-term, effective pharmaceutical treatments and this represents a clinically unmet need. Many forms of hydrocephalus involve dysregulation in water and electrolyte homeostasis, making this an attractive, druggable target.MethodsIn vitro, a combination of electrophysiological and fluid flux assays was used to elucidate secretory transepithelial electrolyte and fluid flux in a human cell culture model of the choroid plexus epithelium and to determine the involvement of serum-, glucocorticoid-induced kinase 1 (SGK1). In vivo, MRI studies were performed in a genetic rat model of hydrocephalus to determine effects of inhibition of SGK1 with a novel inhibitor, SI113.ResultsIn the cultured cell line, SI113 reduced secretory transepithelial electrolyte and fluid flux. In vivo, SI113 blocks the development of hydrocephalus with no effect on ventricular size of wild-type animals and no overt toxic effects. Mechanistically, the development of hydrocephalus in the rat model involves an increase in activated, phosphorylated SGK1 with no change in the total amount of SGK1. SI113 inhibits phosphorylation with no changes in total SGK1 levels in the choroid plexus epithelium.ConclusionThese data provide a strong preclinical basis for the use of SGK1 inhibitors in the treatment of hydrocephalus.

Posthemorrhagic Hydrocephalus in Patients with Subarachnoid Hemorrhage Occurs Independently of CSF Osmolality.

The molecular mechanisms underlying the development of posthemorrhagic hydrocephalus (PHH) remain incompletely understood. As the disease pathogenesis often cannot be attributed to visible cerebrospinal fluid (CSF) drainage obstructions, we here aimed to elucidate whether elevated CSF osmolality following subarachnoid hemorrhage (SAH) could potentiate the formation of ventricular fluid, and thereby contribute to the pathological CSF accumulation observed in PHH. The CSF osmolality was determined in 32 patients with acute SAH after external ventricular drainage (EVD) placement and again upon EVD removal and compared with the CSF osmolality from 14 healthy control subjects undergoing vascular clipping of an unruptured aneurism. However, we found no evidence of elevated CSF osmolality or electrolyte concentration in patients with SAH when compared to that of healthy control subjects. We detected no difference in CSF osmolality and electrolyte content in patients with successful EVD weaning versus those that were shunted due to PHH. Taken together, elevated CSF osmolality does not appear to underlie the development of PHH following SAH. The pathological CSF accumulation observed in this patient group must thus instead be attributed to other pathological alterations associated with the abnormal presence of blood within the CSF compartments following SAH.

Effectiveness of 30o Head Elevation Intervention on Head Pain Levels in Patients with Space Occupying Lesion (SOL) Intracranial Tumor Post-Op Craniotomy : Case Study

ABSTRACT Intracranial tumors are abnormal mass growths in the brain that originate from tissue that grows and divides uncontrollably. Space Occupying Lesion (SOL) is a space pressure caused by an increase in volume within the brain due to the accumulation of blood, cerebro-spinal fluid or brain tissue. A common treatment for intracranial tumors is craniotomy. According to research, about 60% of patients who undergo craniotomy experience moderate to high levels of headache pain. Non-pharmacological pain management that can be done includes deep breathing interventions with guided imagery techniques, monitoring patient hemodynamics and 30o head elevation. The purpose of this study was to present the effect of 30o head elevation nursing intervention on pain levels in patients with SOL intracranial tumors post craniotomy. The method in this study used a case study design conducted in November 2022 at Sumedang Regional General Hospital. The results showed that head elevation of 30o can reduce head pain levels because it can maximize the entry of oxygen into the intracranial and increase the return flow of blood from the brain to the heart, help activate the parasympathetic nervous system which functions to control various activities of the human body at rest and maximize relaxed conditions in patients, resulting in a stable pulse frequency, respiratory frequency, blood pressure. The intervention of elevating the head position or head elevation of 30o is one of the many nonpharmacological therapies that are useful for improving intracranial pressure so that the headache felt by the patient improves and cerebral perfusion can be resolved. Keywords: SOL, Post-op Craniotomy, Head Elevation

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.

Evaluation of Overshunting between Low and Medium Pressure Ventriculoperitoneal Shunts in Dogs with Severe Hydrocephalus Using Frameless Stereotactic Ventricular Shunt Placement

Hydrocephalus is a neurological disorder characterized by an abnormal accumulation of cerebrospinal fluid (CSF) within the ventricular system of the brain, leading to cerebral ventricular dilation, brain parenchyma compression, and neuronal cell loss. Surgery is an effective method of draining excessive amounts of CSF. Ventriculoperitoneal shunt (VPS) allows excess CSF to divert into the abdomen; this device is the most commonly used in the treatment of hydrocephalus both in veterinary and human patients. This study aims to describe the application of two types of VPS, low-pressure valve and medium-pressure valve, using a frameless stereotactic neuronavigational system in eight severe hydrocephalus in dogs and, in particular, analyze the prevalence of postoperative overshunting. Non-communicating hydrocephalus was found in seven dogs, whereas the rest of them had communicating hydrocephalus caused by traumatic brain injury with a skull fracture. The criteria for pressure valve selection depended on the intraoperative intraventricular pressure (IVP) that was determined by the adaptive manometer, according to the human protocol. Low-pressure valve placement was performed in five dogs, and the others received medium-pressure valve placement. The follow-up period was 2 weeks, 4–12 weeks, and 12 weeks to 12 months. Pre- and postoperative information including neurological signs, CT-Scan or MRI, medical treatment, complications, and ventricular volume were compared in all dogs. Seven dogs showed neurological improvement within 2 weeks after surgery. Overshunting was seen in four dogs who received low-pressure valve placement. Three of them had shunt infections within 4 to 6 weeks after surgery. One dog underwent shunt revision from a low-pressure valve to a medium-pressure valve caused by severe overshunting and progressive neurological signs. In addition, cognitive and learning improvements were evaluated based on the owners’ feedback, and neurological signs were examined during the follow-up period in two dogs that received low-pressure valve placement. We conclude that a medium-pressure valve is recommended for overshunting prevention. However, low-pressure valve placement seems to improve cognitive function and learning ability, which is related to an increase in the brain parenchyma observed during long-term monitoring. Moreover, we also report our experience and surgical procedure for frameless stereotactic ventricular shunt placement (FSVSP) in VPS surgery in dogs affected by hydrocephalus.

Biomechanical effects of hyper-dynamic cerebrospinal fluid flow through the cerebral aqueduct in idiopathic normal pressure hydrocephalus patients

Normal pressure hydrocephalus (NPH) is an intracranial disease characterized by an abnormal accumulation of cerebrospinal fluid (CSF) in brain ventricles within the normal range of intracranial pressure. Most NPH in aged patients is idiopathic (iNPH) and without any prior history of intracranial diseases. Although an abnormal increase of CSF stroke volume (hyper-dynamic CSF flow) in the aqueduct between the third and fourth ventricles has received much attention as a clinical evaluation index in iNPH patients, the biomechanical effects of this flow on iNPH pathophysiology are poorly understood. This study aimed to clarify the potential biomechanical effects of hyper-dynamic CSF flow through the aqueduct of iNPH patients using magnetic resonance imaging-based computational simulations. Ventricular geometries and CSF flow rates through aqueducts of 10 iNPH patients and 10 healthy control subjects were obtained from multimodal magnetic resonance images, and these CSF flow fields were simulated using computational fluid dynamics. As biomechanical factors, we evaluated wall shear stress on the ventricular wall and the extent of flow mixing, which potentially disturbs the CSF composition in each ventricle. The results showed that the relatively high CSF flow rate and large and irregular shapes of the aqueduct in iNPH resulted in large wall shear stresses localized in relatively narrow regions. Furthermore, the resulting CSF flow showed a stable cyclic motion in control subjects, whereas strong mixing during transport through the aqueduct was found in patients with iNPH. These findings provide further insights into the clinical and biomechanical correlates of NPH pathophysiology.

Chromosome 19 polygenic risk scores defined by deep learning model predict the rate of Alzheimer’ disease progression

AbstractBackgroundGenetic variants invariably play a crucial role in rate of disease progression. The effects of Alzheimer’s disease (AD) genetic risk factors on disease progression remains poorly understood. We developed a novel deep learning framework that could identify a personalized polygenic risk score (PRS) at the individual chromosomal level. We further used the individual’s PRS to predict the rate of cognitive decline and cerebrospinal fluid (CSF) biomarker changes.MethodWe applied a novel deep learning model to the 266,161 SNP chromosome 19 data of 313 AD and 457 cognitively unimpaired (CU) ADNI patients. The top 35 AD‐determining SNPs were determined and validated in an external dataset. Next, we used multiple regression to analyze the contribution of each combination of 3/35 SNPs to predict the rate of CSF accumulation (amyloid beta (Aβ), tau, phosphorylated tau (pTau), Aβ /tau, and Aβ/pTau) and the rate of cognitive decline in the memory, language, executive functioning, and visuospatial domains while controlling for age, sex, and education.ResultAll regression models were significant at the 0.05 level. The R‐squared adjusted values for each of the CSF models listed above were 0.917, 0.845, 0.902, 0.939, and 0.878, respectively. The majority of SNPs selected for the CSF regression models mapped to APOC1, APOC2, and TOMM40. The R‐squared adjusted values for the cognitive models were 0.188, 0.215, 0.436, and 0.266, respectively. The selected SNPs mapped to APOC1, TOMM40, VRK3, and NECTIN2. Given the less robust predictive power for cognitive change over time we increased the search to the top 150 AD SNPs. This produced R‐squared adjusted values of 0.426, 0.437, 0.607, and 0.557, respectively. The selected SNPS mapped to TOMM40, APOC1P1, ERCC1, IGSF23, ZNF556, CKM, APOC2, ZNF473, and CEACAM22P.ConclusionOur deep learning model PRS can successfully predict the AD cognitive and biomarker changes over time. Our model’s capability in deciphering the impact of SNPs on AD development could prove critical for early presymptomatic risk assessment and personalized therapeutic strategy approaches.

Endoscopic Fenestration of an Intra-ventricular Arachnoid Cyst in a Young Male – A Rare Entity

Introduction: Among intracranial space-occupying lesions, arachnoid cysts compromise 1% only. Abnormal collection of cerebrospinal fluid occurs in these types of cysts leading to pressure symptoms. Developmental abnormalities of cerebrospinal structures in early fetal life lead to the primary type of arachnoid cysts, while the second type of arachnoid cyst is formed after some neurological insult like head injury, tumor, meningitis, or brain surgery. In 60 – 90% of cases, the primary type predominates and presents with pressure symptoms before the age of 20 years. The adjudged incidence is 1.4% in adults, the least frequent being intraventricular location. Clinical Case: A 23-year-old male presented with a long-standing left-sided cranial vault headache, right-sided focal seizures, and progressive right- hemiparesis. Neurological evaluation revealed upper motor neuron signs on the right side of the body. A computerized axial tomography raised the suspicion of an arachnoid cyst for which magnetic resonance imaging was done which revealed a large intraventricular cyst of lateral ventricles causing mass effect over the ipsilateral hemisphere and mild obstructive hydrocephalous. Surgical intervention was required as per symptomology (intractable headache, seizures, and hemiparesis) and large cyst size. Conclusion: Cerebrospinal fluid accumulation in the brain's arachnoid layer causes non-cancerous arachnoid cysts. Larger cysts may push on brain tissue and cause neurological difficulties. MRI may diagnose arachnoid cysts, and treatment options include cystoperitoneal shunt, craniotomy, and neuro-endoscopic fenestration, the least invasive. Cyst size and location determine therapy. In this example, endoscopic treatment reduced symptoms and consequences.

Brain-Derived Major Glycoproteins Are Possible Biomarkers for Altered Metabolism of Cerebrospinal Fluid in Neurological Diseases

Cerebrospinal fluid (CSF) plays an important role in the homeostasis of the brain. We previously reported that CSF major glycoproteins are biosynthesized in the brain, i.e., lipocalin-type prostaglandin D2 synthase (L-PGDS) and transferrin isoforms carrying unique glycans. Although these glycoproteins are secreted from distinct cell types, their CSF levels have been found to be highly correlated with each other in cases of neurodegenerative disorders. The aim of this study was to examine these marker levels and their correlations in other neurological diseases, such as depression and schizophrenia, and disorders featuring abnormal CSF metabolism, including spontaneous intracranial hypotension (SIH) and idiopathic normal pressure hydrocephalus (iNPH). Brain-derived marker levels were found to be highly correlated with each other in the CSF of depression and schizophrenia patients. SIH is caused by CSF leakage, which is suspected to induce hypovolemia and a compensatory increase in CSF production. In SIH, the brain-derived markers were 2-3-fold higher than in other diseases, and, regardless of their diverse levels, they were found to be correlated with each other. Another abnormality of the CSF metabolism, iNPH, is possibly caused by the reduced absorption of CSF, which secondarily induces CSF accumulation in the ventricle; the excess CSF compresses the brain's parenchyma to induce dementia. One potential treatment is a "shunt operation" to bypass excess CSF from the ventricles to the peritoneal cavity, leading to the attenuation of dementia. After the shunt operation, marker levels began to increase within a week and then further increased by 2-2.5-fold at three, six, and twelve months post-operation, at which point symptoms had gradually attenuated. Notably, the marker levels were found to be correlated with each other in the post-operative period. In conclusion, the brain-derived major glycoprotein markers were highly correlated in the CSF of patients with different neurological diseases, and their correlations were maintained even after surgical intervention. These results suggest that brain-derived proteins could be biomarkers of CSF production.

Reduction of Porencephalic Cyst Along with the Revival of Motor Control Using the Deep Brain Sound Stimulation (DBSS) Technology as a Novel Approach

A porencephalic cyst is a rare disorder, with the etiology of brain parenchymal loss as a result of perinatal cerebral ischemia or hemorrhage leading to the accumulation of cerebrospinal fluid within the parenchyma. It is diagnosed radiologically, and management depends on the clinical manifestations. The present case depicts a porencephalic cyst presenting with cerebral right-sided hemiparesis in adulthood. The cyst dimensions measured 2.6*0.6*0.5 cm in the left lateral ventricle with associated hemiparesis of the right side at the time of the first MRI scan before Deep Brain Sound Stimulation (DBSS) sessions. A reduction in the size of the cyst to 16*7*7 mm and then to a subsequent 8 mm was documented during a novel, non-invasive deep brain stimulation via sound (DBSS) treatment. In addition, right upper and lower limb power increased to 5/5 with improved coordination in a complete neurological evaluation. DEXA scan showed an increased bone density and muscle bulk.

Glymphatic system dysfunction in pediatric acute lymphoblastic leukemia without clinically diagnosed central nervous system infiltration: a novel DTI-ALPS method.

Central nervous system (CNS) infiltration commonly occurs in children with acute lymphoblastic leukemia (ALL). Nevertheless, CNS infiltration is rarely detected at the initial diagnosis. The glymphatic system, which regulates cerebrospinal fluid (CSF) and interstitial fluid transport, is considered one of the possible routes of CNS infiltration by leukemia cells. In this study, we used diffusion tensor image analysis along the perivascular space (DTI-ALPS) method to investigate glymphatic system function and obtained CSF volume using synthetic magnetic resonance imaging (SyMRI) in pediatric ALL without clinically diagnosed CNS infiltration. Twenty-nine ALL and 29 typically developing (TD) children were prospectively recruited (age 4-16years) in the present study. Group differences in brain volumetric parameters, brain water diffusivities, and the ALPS index were evaluated after controlling for age, gender, and handedness. Furthermore, significant group-different parameters were correlated with clinical information using partial correlations analysis. Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all pFDR-corrected < 0.05). Moreover, the ALPS index was negatively associated with the risk classification (r = - 0.59, pFDR-corrected = 0.04) in pediatric ALL. Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration. These novel findings suggested that the glymphatic system might be essential in the early-stage process of ALL CNS infiltration, which provides a new direction for exploring underlying mechanisms and early detection of pediatric ALL CNS infiltration. • Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all pFDR-corrected < 0.05). • The ALPS index was negatively associated with the risk classification (r = -0.59, pFDR-corrected = 0.04) in pediatric ALL. • Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration, which suggested that the ALPS index and CSF volume might be promising imaging markers for early detection of pediatric ALL CNS infiltration.

Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K+] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.

Novel concepts in the pathogenesis of hydrocephalus.

Hydrocephalus is a multifactorial neurological disorder and one of the most common neurosurgical conditions characterized by excessive cerebrospinal fluid (CSF) accumulation within the brain's ventricles. It can result in dilatation of the ventricular system caused by the inadequate passage of CSF from its point of production within the ventricles to its point of absorption into the systemic circulation. Recent findings on the genetics and molecular studies of hydrocephalus have the potential to improve treatment and quality of life. Review of literature on the novel studies of the pathogenesis of hydrocephalus. Molecular studies on the pathogenesis of hydrocephalus have provided a means to improve the treatment and follow-up of patients with hydrocephalus.

Bi-allelic variations in CRB2, encoding the crumbs cell polarity complex component 2, lead to non-communicating hydrocephalus due to atresia of the aqueduct of sylvius and central canal of the medulla

Congenital hydrocephalus is a common condition caused by the accumulation of cerebrospinal fluid in the ventricular system. Four major genes are currently known to be causally involved in hydrocephalus, either isolated or as a common clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. Here, we report 3 cases from 2 families with congenital hydrocephalus due to bi-allelic variations in CRB2, a gene previously reported to cause nephrotic syndrome, variably associated with hydrocephalus. While 2 cases presented with renal cysts, one case presented with isolated hydrocephalus. Neurohistopathological analysis allowed us to demonstrate that, contrary to what was previously proposed, the pathological mechanisms underlying hydrocephalus secondary to CRB2 variations are not due to stenosis but to atresia of both Sylvius Aqueduct and central medullar canal. While CRB2 has been largely shown crucial for apico-basal polarity, immunolabelling experiments in our fetal cases showed normal localization and level of PAR complex components (PKCι and PKCζ) as well as of tight (ZO-1) and adherens (β-catenin and N-Cadherin) junction molecules indicating a priori normal apicobasal polarity and cell–cell adhesion of the ventricular epithelium suggesting another pathological mechanism. Interestingly, atresia but not stenosis of Sylvius aqueduct was also described in cases with variations in MPDZ and CCDC88C encoding proteins previously linked functionally to the Crumbs (CRB) polarity complex, and all 3 being more recently involved in apical constriction, a process crucial for the formation of the central medullar canal. Overall, our findings argue for a common mechanism of CRB2, MPDZ and CCDC88C variations that might lead to abnormal apical constriction of the ventricular cells of the neural tube that will form the ependymal cells lining the definitive central canal of the medulla. Our study thus highlights that hydrocephalus related to CRB2, MPDZ and CCDC88C constitutes a separate pathogenic group of congenital non-communicating hydrocephalus with atresia of both Sylvius aqueduct and central canal of the medulla.

VP shunt entry area recommender (VPSEAR): A computer-assisted system for VP shunt operation

Hydrocephalus is a condition with an abnormal cerebrospinal fluid (CSF) accumulation in the brain's ventricles resulting in ventricular enlargement. One of the most common surgical treatments for hydrocephalus is the ventriculoperitoneal (VP) Shunt operation. A freehand technique using surface anatomy ventricular catheter placement has been widely used in VP Shunt operations because of its simplicity and low cost. However, this technique trades off with moderate accuracy. To improve accuracy, most existing freehand techniques involved using tools or software to manually measure distances and/or drilling angles from CT or MRI slides. In this work, we developed the first fully automated system VP shunt entry area recommender (VPSEAR) for a pre-planned freehand placement. The program with a user- interface took the patient's CT slides, calculated a circular entry site on a skull, and reported a unique circular entry region. The program integrated several mathematical knowledge and 3-D data processing techniques to ensure high accuracy and acceptable running time. We tested the invented programs on a collection of CT slices of 15 patients with 30 head sides and evaluated the system's accuracy against the traditional Keen's method using 3D Slicer software. We achieved an average accuracy of 95.33% using five internal points evaluation, with accuracy improvement over Keen's method up to 40.33%. The program running time was less than 15 min per head side.