Search

BACKGROUND Transsphenoid meningoencephalocele is a congenital anomaly formed by herniation of an ependyma delimited sac through a bony defect into the sphenoid sinus. The sac contains cerebrospinal fluid and neurovascular structures. The prevalence of transsphenoid meningoencephalocele in the adult population is rare. It usually manifests as nasal liquorrhoea. METHODS AND RESULTS This case report presents an adult male who underwent surgery due to suspected pituitary macroadenoma. The surgery was performed endoscopically via the transnasal approach with a surprising finding of true transsphenoid meningoencephalocele. Ectopic solid tissue was found in the sphenoid sinus in which pituitary adenoma was histologically confirmed. CONCLUSION This paper presents a previously unpublished combination of true transsphenoid meningoencephalocele and pituitary adenoma in an adult individual.

The current study was designed to give a complete microscopic description of the ependymal cells of the one-humped camel (Camelus dromedarius) using histological, immunohistochemical, and transmission microscopic descriptions of the ependymal cells of the fresh 35 spinal cord samples immediately after their slaughtering. In our findings, the central canal of the spinal cord was lined by multilayered stratified cuboidal or columnar ependymal cells. The ependymal cells had an irregular striated border at their free surface. The ependymal cells do not exhibit a basement membrane. The simple oval nucleus was occupied a large part of the cell with spherical mitochondria. The apical surface of the ependymal cells possesses long cilia; each cilium was bounded by an evagination of the luminal plasma membrane. Some ependymal cells had minute finger-like projections on their luminal plasma membrane. In the perinuclear zone of ependymal cells, many cristiform mitochondria, free ribosomes, and Golgi complexes usually occur. Vacuoles with homogenous and clear fluid were observed. The lateral surface of the adjacent ependymal cells exhibits several tight junctions represented by zonulae occludens and adherens. There were many desmosomes between the neighboring ependymal cells. A perinuclear whorl of filaments fills the lateral part of these ependymal cells. The ependymal cells revealed a clear immunohistochemical reaction with proliferating cell nuclear antigen and nestin stain. There were no obvious differences between the different segments of the spinal cord. Our data concluded that the ependymal cells display clear differences in anatomy as well as ultrastructure that may reflect their distinct functional activity.

It has been commonly accepted for a long time that the cerebrospinal fluid (CSF) drains into arachnoid granulations from the subarachnoid space to the dural venous sinus unidirectionally. However, recently, periventricular capillaries and lymphatic concepts have been introduced. The CSF moves along the perivascular space and drains into the capillary vessels or meningeal lymphatic tissues. CSF is involved in removing brain waste out of the brain. In this study, we investigated the outflow mechanism of substances in the CSF from the brain. We investigated the movement of CSF by injection of gold colloid conjugates (2, 40, and 200 nm) into the lateral ventricles of mouse fetuses and evaluated the deposition by silver stain with tissue transparency and electron microcopy. Cadaverine was also injected into the lateral ventricle to determine its movement tract. The gold particle deposition was mainly observed in the frontal skull base. Electron microscopic study showed that the gold particle deposition was observed on the choroid plexus and ependyma in the lateral ventricle and also red blood cells in the heart and liver. Two-nanometer particles were exclusively observed in the liver. Cadaverine injection study demonstrated that cadaverine was observed at the extracranial frontal skull base, choroid plexus, ependymal surface, and perivascular area in the brain white matter. The particles in the CSF were shown to move from the brain to the frontal skull base and also into the blood stream through the choroid plexus in the fetus. The outflow of particles in the CSF may be regulated by molecular size. This new information will contribute to the prevention of brain degeneration due to brain waste deposition.

Purpose Since a case of hydrocephalus in humans considered to be caused by ciliary dysfunction was first reported by Greenstone et al. in 1984, numerous papers on the correlation between ciliary function and hydrocephalus have been published. Methods We reviewed the published literature on primary ciliary dyskinesia in humans causing hydrocephalus, focusing on articles specifically examining the relation between ciliary function and hydrocephalus and its treatment. In addition, the authors’ experience is briefly discussed. Results Full texts of 16 articles reporting cases of human hydrocephalus (including ventriculomegaly) due to defects in ependymal ciliary function or primary ciliary dyskinesia observed in clinical practice were extracted. In recent years, studies on animal models, especially employing knockout mice, have revealed genetic mutations that cause hydrocephalus via ciliary dysfunction. However, a few reports on the onset of hydrocephalus in human patients with primary ciliary dyskinesia have confirmed that the incidence of this condition was extremely low compared to that in animal models. Conclusion In humans, it is rare for hydrocephalus to develop solely because of abnormalities in the cilia, and it is highly likely that other factors are also involved along with ciliary dysfunction.

Iron accumulation in the CNS is associated with many neurological diseases via amplification of inflammation and neurodegeneration. However, experimental studies on iron overload are challenging, since rodents hardly accumulate brain iron in contrast to humans. Here, we studied LEWzizi rats, which present with elevated CNS iron loads, aiming to characterise choroid plexus, ependymal, CSF and CNS parenchymal iron loads in conjunction with altered blood iron parameters and, thus, signifying non‐classical entry sites for iron into the CNS. Non‐haem iron in formalin‐fixed paraffin‐embedded tissue was detected via DAB‐enhanced Turnbull Blue stainings. CSF iron levels were determined via atomic absorption spectroscopy. Ferroportin and aquaporin‐1 expression was visualised using immunohistochemistry. The analysis of red blood cell indices and serum/plasma parameters was based on automated measurements; the fragility of red blood cells was manually determined by the osmotic challenge. Compared with wild‐type animals, LEWzizi rats showed strongly increased iron accumulation in choroid plexus epithelial cells as well as in ependymal cells of the ventricle lining. Concurrently, red blood cell macrocytosis, low‐grade haemolysis and significant haemoglobin liberation from red blood cells were apparent in the peripheral blood of LEWzizi rats. Interestingly, elevated iron accumulation was also evident in kidney proximal tubules, which share similarities with the blood–CSF barrier. Our data underscore the importance of iron gateways into the CNS other than the classical route across microvessels in the CNS parenchyma. Our findings of pronounced choroid plexus iron overload in conjunction with peripheral iron overload and increased RBC fragility in LEWzizi rats may be seminal for future studies of human diseases, in which similar constellations are found., LEWzizi rats present with pronounced choroid plexus iron overload in conjunction with elevated levels of iron and cell‐free haemoglobin in the blood and increased RBC fragility. In several human diseases of diverse aetiologies, a pronounced accumulation of iron in choroid plexuses has already been described. Our study highlights the importance of choroid plexuses as iron entry sites into the CNS and their linkage with peripheral iron loads and alterations in red blood cell biology.

The generation of inhibitory interneurons from neural stem cells in the subependymal zone is regulated by trophic factors. Reduced levels of trophic factors are associated with inhibitory interneuron dysfunction in the prefrontal cortex and hippocampus in psychiatric disorders, yet the extent to which altered trophic support may underpin deficits in inhibitory interneuron generation in the neurogenic niche remains unexplored in schizophrenia and bipolar disorder. We determined whether the expression of ligands, bioavailability-regulating binding proteins, and cognate receptors of 4 major trophic factor families (insulin-like growth factor [IGF], epidermal growth factor [EGF], fibroblast growth factor [FGF], and brain-derived neurotrophic factor [BDNF]) are changed in schizophrenia and bipolar disorder compared to controls. We used robust linear regression analyses to determine whether altered expression of trophic factor family members predicts neurogenesis marker expression across diagnostic groups. We found that IGF1 mRNA was decreased in schizophrenia and bipolar disorder compared with controls (P ≤ .006), whereas both IGF1 receptor (IGF1R) and IGF binding protein 2 (IGFBP2) mRNAs were reduced in schizophrenia compared with controls (P ≤ .02). EGF, FGF, and BDNF family member expression were all unchanged in both psychiatric disorders compared with controls. IGF1 expression positively predicted neuronal progenitor and immature neuron marker mRNAs (P ≤ .01). IGFBP2 expression positively predicted neural stem cell and neuronal progenitor marker mRNAs (P ≤ .001). These findings provide the first molecular evidence of decreased IGF1, IGF1R, and IGFBP2 mRNA expression in the subependymal zone in psychiatric disorders, which may potentially impact neurogenesis in schizophrenia and bipolar disorder.

Background A small, incidental filar cyst associated with terminal lipoma is thought to be caused by failure of secondary neurulation; however, the precise embryologic background is not fully understood. Retained medullary cord (RMC) also originates from late arrest of secondary neurulation. The central feature of RMC histopathology is a central canal-like ependyma-lined lumen with surrounding neuroglial core. Case Description We surgically treated 2 patients with a large cyst in the rostral part of the filum and lipoma in the caudal filum. At cord untethering surgery, the filum was severed at the caudal part of the cyst. Histopathologically, the filar cyst was the cystic dilatation of the central canal-like structure at the marginal part of the lipoma. The central canal-like structure was continuous caudally in the lipoma, and its size decreased toward the caudal side. Conclusions The present findings support the idea raised by Pang et al that entities such as filar cyst, terminal lipomas, and RMC can all be considered consequences of a continuum of regression failure occurring during late secondary neurulation.

Different cellular constituents of the central nervous system occurring in encephaloceles or neuroglial heterotopias (NGHs) have been reported, but the ependymal morphology has rarely been described in the previous literature, let alone the related histological images. To determine the ependymal morphology in encephaloceles or NGHs, we report a rare case of encephalocele with numerous ependymal components. Radiological examination showed that a 6.2 × 3.1 cm nasal dorsum mass-forming encephalocele in a 24-year-old woman, who had an intracranial connection through a frontal bone defect. This patient underwent a resection of the encephalocele under nasal endoscopy and a reconstruction of the cranial base. The patient had a good prognosis with no postoperative complications during follow-up. Microscopically, the ependymal components entrapped in a collagenized background showed numerous slit-like spaces lined by columnar cells with abundant palely eosinophilic cytoplasm and apical surface microvilli. With immunohistochemistry, in addition to the expression of EMA along with the slit-like spaces, GFAP and S100 were diffusely expressed in the slit-like spaces. In conclusion, the ependymal component in either encephaloceles or NGHs may present slit-like spaces arranged in an anastomosing pattern. The unusual morphology of ependyma continues to be underrecognized by pathologists and is easily misdiagnosed; therefore, an awareness of the morphological change in ependyma is necessary.

Neuroendoscopic biopsy represents the procedure of choice for pure intraventricular lesions. Instead, in case of deep-seated paraventricular tumors, with intact ependyma, the advantage of neuroendoscopy over stereotactic biopsy is not so evident, because the lesion is not under direct vision; the tissue sample may be limited to more superficial ependymal layer, and bleeding may obscurate vision. Also, stereotactic biopsy may reserve additional problems for these lesions: inaccuracy caused by leak of cerebrospinal fluid and increased risk of severe hemorrhage due to damage of the ependymal vessels. We report two cases of young children affected by thalamic tumors that were biopsied using a modification of a recently proposed technique: endoscopic visual control, neuronavigated needle biopsy. This technique may combine the accuracy of a stereotactic needle biopsy with the advantage of visual control on site of ependymal puncture and possibility of immediate bleeding control.

Choroid plexus (CP) may aid brain development and repair by secreting growth factors and neurotrophins for CSF streaming to ventricular and subventricular zones. Disrupted ventricular/subventricular zone progenitors and stem cells lead to CNS maldevelopment. Exploring models, we organ cultured the CP and transplanted fresh CP into a lateral ventricle of postnatal hydrocephalic (hyHTx) and nonhydrocephalic (nHTx) rats. After 60 days in vitro, the cultured choroid ependyma formed spherical rings with beating cilia. Cultured CP expressed endocytotic caveolin 1 and apical aquaporin 1 and absorbed horseradish peroxidase from medium. Transthyretin secretory protein was secreted by organ-cultured CP into medium throughout 60 days in vitro. Fresh CP, surviving at 1 week after lateral ventricle implantation of nHTx or hyHTx did not block CSF flow. Avascular 1-week transplants in vivo expressed caveolin 1, aquaporin 1, and transthyretin, indicating that grafted CP may secrete trophic proteins but not CSF. Our findings encourage further exploration on CP organ culture and grafting for translational strategies. Because transplanted CP, though not producing CSF, may secrete beneficial molecules for developing brain injured by hydrocephalus, we propose that upon CP removal in hydrocephalus surgery, the fractionated tissue could be transplanted back (ventricular autograft).

Background Second Window Indocyanine Green (SWIG) is a novel technique for real-time, intraoperative tumor visualization using a high-dose infusion of indocyanine green (ICG) 24 hours before surgery. Due to pathologic diversity found in the pineal region, tissue diagnosis in patients with pineal region mass is essential to optimize further clinical management. Case Description We present the case of a 75-year-old woman with known pineal region mass for 18 years, who presented with progressive classic signs and symptoms of obstructive hydrocephalus over the past 6 months. Preoperative imaging confirmed a contrast-enhancing pineal region tumor, which appeared to be obstructing the aqueduct of Sylvius, causing proximal obstructive hydrocephalus. We delivered 5 mg/kg of ICG intravenously 24 hours before the surgery. The patient underwent an endoscopic third ventriculostomy and a biopsy of the pineal lesion. The tumor demonstrated clear near-infrared fluorescence, which was distinct from surrounding third ventricle floor and ependyma. The signal-to-background ratio was 2.9. The final pathology report revealed a World Health Organization grade I pineocytoma. Conclusions We report on a novel application of near-infrared fluorescence for tumor identification of pineal region tumors, using the “SWIG technique.”

Background: The choroid plexus (CP) consists of specialized ependymal cells and underlying stroma and blood vessels, producing the bulk of the cerebrospinal fluid (CSF). CP epithelial cells are the site of the internal blood-cerebrospinal fluid barrier, show epithelial characteristics (basal lamina, tight junctions), and express aquaporin-1 (AQP1) apically. In contrast, ventricle-lining ependymal cells express aquaporin-4 (AQP4) basolaterallly. The initial purpose of this study was to analyze the expression of aquaporins in the ependyma – CP transition zone in the human brain to gain insights in aquaporin regulation. The results prompted us to investigate aquaporin expression in the mouse CP of different age groups. Methods: We analyzed the CP from eight body donors (age 74-91) applying immunofluorescence, qPCR, and freeze-fracture electron microscopy. We used antibodies against AQP1, AQP4, NKCC1, and Na/K-ATPase. In addition, we compared the CP from young (2 months), adult (12 months) and old (30 months) mice by qPCR and immunofluorescence. Results: Unexpectedly, many cells in the human CP were positive not only for AQP1 but also for AQP4, normally restricted to ependymal cells and astrocytes. Expression of AQP1 and AQP4 was found in the CP of all eight body donors. These results were confirmed by qPCR, and by electron microscopy detecting AQP4-specific orthogonal arrays of particles. To find out whether AQP4 expression correlated with relevant transport-related proteins we investigated expression of NKCC1 and Na/K-ATPase. Immunostaining for NKCC1 was similar to AQP1 and revealed no particular pattern related to AQP4. Co-staining of AQP4 and Na/K-ATPase indicated a trend for an inverse correlation of their expression. To test for the possibility of age-related changes causing AQP4 expression in the CP, we analyzed mouse brains from different age groups and found a significant increase of AQP4 on the mRNA level in old mice compared to young and adult animals. Conclusions: We provide evidence for AQP4 expression in the human and murine CP related to aging which likely contributes to the water flow through the CP epithelium and CSF production. In two alternative hypotheses, we discuss this as a beneficial compensatory, or a detrimental mechanism influencing the previously observed CSF changes during aging.

BackgroundIntraventricular penetration is rare in glioblastoma (GBM). Whether the ependymal region including the ependyma and subventricular zone (SVZ) can prevent GBM invasion remains unclear.MethodsMagnetic resonance imaging (MRI) and haematoxylin–eosin (HE) staining were performed to evaluate the size and anatomical locations of GBM. Binary logistic regression analysis was used to assess the correlation between tumor-ependyma contact, ventricle penetration and clinical characteristics. Cell migration and invasion were assessed via Transwell assays and an orthotopic transplantation model.ResultsAmong 357 patients with GBM, the majority (66%) showed ependymal region contact, and 34 patients (10%) showed ventricle penetration of GBM. GBM cells were spread along the ependyma in the orthotopic transplantation model. The longest tumor diameter was an independent risk factor for GBM-ependymal region contact, as demonstrated by univariate (OR = 1.706, p < 0.0001) and multivariate logistic regression analyses (OR = 1.767, p < 0.0001), but was not associated with ventricle penetration. Cerebrospinal fluid (CSF) could significantly induce tumor cell migration (p < 0.0001), and GBM could grow in CSF. Compared with those from the cortex, cells from the ependymal region attenuated the invasion of C6 whether cocultured with C6 or mixed with Matrigel (p = 0.0054 and p = 0.0488). Immunofluorescence analysis shows a thin gap with GFAP expression delimiting the tumor and ependymal region.ConclusionThe ependymal region might restrict GBM cells from entering the ventricle via a non-mechanical force. Further studies in this area may reveal mechanisms that occur in GBM patients and may enable the design of new therapeutic strategies.

Key Clinical Message Though typical dysembryoplastic neuroepithelial tumors (DNETs) are located in the cerebral cortex, an atypical DNET could occur in the temporal horn of the lateral ventricle and broadly involve the ependyma. Awareness of this atypical form of DNET is of value for the wright diagnosis and management of atypical DNETs., Though typical dysembryoplastic neuroepithelial tumors (DNETs) are located in the cerebral cortex, an atypical DNET could occur in the temporal horn of the lateral ventricle and broadly involve the ependyma. Awareness of this atypical form of DNET is of value for the wright diagnosis and management of atypical DNETs.

Dissemination of glioma in humans can occur as leptomeningeal nodules, diffuse leptomeningeal lesions, or ependymal lesions. Cerebrospinal fluid (CSF) drop metastasis of glioma is not well-recognized in dogs. Ten dogs with at least two anatomically distinct and histologically confirmed foci of glioma were included in this study. The 10 dogs underwent 28 magnetic resonance imaging (MRI) examinations, with distant CSF drop metastasis revealed in 13 MRIs. The CSF drop metastases appeared as leptomeningeal nodules in four dogs, diffuse leptomeningeal lesions in six dogs, and ependymal lesions in seven dogs; six dogs had a combination of lesion types. Primary tumors were generally T2-heterogeneous and contrast-enhancing. Many metastases were T2-homogeneous and non-enhancing. Diffuse leptomeningeal lesions were seen as widespread extra-axial contrast-enhancement, again very dissimilar to the intra-axial primary mass. Primary masses were rostrotentorial, whereas metastases generally occurred in the direction of CSF flow, in ventricles, CSF cisterns, and the central canal or leptomeninges of the cervical or thoracolumbar spinal cord. Seven of the dogs had received therapy limited to the primary mass, such as surgery or stereotactic radiation, then developed metastasis in the following months. CSF drop metastasis of glioma may take a very different appearance on MRI to the primary mass, including periventricular lesions that are more homogeneous and less contrast-enhancing, rostral horn signal changes, or leptomeningeal enhancement ventral to the brainstem or encircling the spinal cord.

Background: Closed spinal dysraphism of primary neurulation failure could be associated with filar anomalies, such as filar lipoma or thickened and tight filum terminale (TFT), resulting from impaired secondary neurulation. Retained medullary cord (RMC) is a remnant of the cavitary medullary cord originating from the secondary neurulation failure. Some filar lipomas are known to contain a central canal-like ependyma-lined lumen with surrounding neuroglial tissues (E-LC w/NGT), that is, a characteristic histopathology of RMC. To clarify the embryological background of these filar anomalies, we evaluated the histopathological findings. Methods: Among 41 patients with lesions of primary neurulation failure who underwent initial untethering surgery, the filum including cord-like structure (C-LS) was additionally resected in 10 patients (five dorsal and transitional lipomas; five limited dorsal myeloschisis). We retrospectively analyzed the clinical, neuroradiological, intraoperative, and histopathological findings. Results: Among 10 patients, two patients were diagnosed with RMC based on morphological features and intraoperative neurophysiological monitoring. The diagnosis of filar lipoma was made in six patients, since various amounts of fibroadipose tissue were histopathologically noted in the filum. Two patients were diagnosed with TFT, since the filum was composed solely of fibrocollagenous tissue. E-LC w/NGT was noted not only in both C-LSs of RMCs but also in two out of six fila both with filar lipomas and fila with TFTs. Conclusion: These findings provide further evidence for the idea that entities, such as filar lipoma, TFT, and RMC, can be considered consequences of a continuum of regression failure occurring during late secondary neurulation.

Idiopathic normal pressure hydrocephalus (iNPH) is considered an age-dependent chronic communicating hydrocephalus associated with cerebrospinal fluid (CSF) malabsorption; however, the aetiology of ventricular enlargement in iNPH has not yet been elucidated. There is accumulating evidence that support the hypothesis that various alterations in CSF dynamics contribute to ventricle dilatation in iNPH. This review focuses on CSF dynamics associated with ventriculomegaly and summarises the current literature based on three potential aetiology factors: genetic, environmental and hydrodynamic. The majority of gene mutations that cause communicating hydrocephalus were associated with an abnormal structure or dysfunction of motile cilia on the ventricular ependymal cells. Aging, alcohol consumption, sleep apnoea, diabetes and hypertension are candidates for the risk of developing iNPH, although there is no prospective cohort study to investigate the risk factors for iNPH. Alcohol intake may be associated with the dysfunction of ependymal cilia and sustained high CSF sugar concentration due to uncontrolled diabetes increases the fluid viscosity which in turn increases the shear stress on the ventricular wall surface. Sleep apnoea, diabetes and hypertension are known to be associated with the impairment of CSF and interstitial fluid exchange. Oscillatory shear stress to the ventricle wall surfaces is considerably increased by reciprocating bidirectional CSF movements in iNPH. Increased oscillatory shear stress impedes normal cilia beating, leading to motile cilia shedding from the ependymal cells. At the lack of ciliary protection, the ventricular wall is directly exposed to increased oscillatory shear stress. Additionally, increased oscillatory shear stress may be involved in activating the flow-mediated dilation signalling of the ventricular wall. In conclusion, as the CSF stroke volume at the cerebral aqueduct increases, the oscillatory shear stress increases, promoting motor cilia shedding and loss of ependymal cell coverage. These are considered to be the leading causes of ventricular enlargement in iNPH.

Background Implantation of ventricular catheters (VCs) to drain cerebrospinal fluid (CSF) is a standard approach to treat hydrocephalus. VCs fail frequently due to tissue obstructing the lumen via the drainage holes. Mechanisms driving obstruction are poorly understood. This study aimed to characterize the histological features of VC obstructions and identify links to clinical factors. Methods 343 VCs with relevant clinical data were collected from five centers. Each hole on the VCs was classified by degree of tissue obstruction after macroscopic analysis. A subgroup of 54 samples was analyzed using immunofluorescent labelling, histology and immunohistochemistry. Results 61.5% of the 343 VCs analyzed had tissue aggregates occluding at least one hole (n = 211) however the vast majority of the holes (70%) showed no tissue aggregates. Mean age at which patients with occluded VCs had their first surgeries (3.25 yrs) was lower than in patients with non-occluded VCs (5.29 yrs, p Conclusion Our data show that age of the first surgery and length of time a VC is implanted are factors that influence the degree of VC obstruction. The tissue aggregates obstructing VCs are composed predominantly of astrocytes and macrophages; microglia have a relatively small presence.

Patients with ovarian cancer and paraneoplastic cerebellar degeneration, a cancer-related immune disorder, often have anti-Yo antibody. Here we studied the distributions of anti-Yo antigens CDR2L and CDR2 in rat and human brain using immunohistochemistry and western blot. CDR2L localized mainly to the Purkinje cells and large neurons scattered in the brain stem. CDR2 was detected in vascular smooth muscle cells of rat and human and in cells lining the ventricle system in rats. The observed distribution of CDR2L is compatible with the hypothesis that this antigen is the major target of anti-Yo. CDR2 and CDR2L are expressed by different cell subtypes.

Progressive forms of multiple sclerosis (MS) are associated with chronic demyelination, axonal loss, neurodegeneration, cortical and deep gray matter damage, and atrophy. These changes are strictly associated with compartmentalized sustained inflammation within the brain parenchyma, the leptomeninges, and the cerebrospinal fluid. In progressive MS, molecular mechanisms underlying active demyelination differ from processes that drive neurodegeneration at cortical and subcortical locations. The widespread pattern of neurodegeneration is consistent with mechanisms associated with the inflammatory molecular load of the cerebrospinal fluid. This is at variance with gray matter demyelination that typically occurs at focal subpial sites, in the proximity of ectopic meningeal lymphoid follicles. Accordingly, it is possible that variations in the extent and location of neurodegeneration may be accounted for by individual differences in CSF flow, and by the composition of soluble inflammatory factors and their clearance. In addition, “double hit” damage may occur at sites allowing a bidirectional exchange between interstitial fluid and CSF, such as the Virchow–Robin spaces and the periventricular ependymal barrier. An important aspect of CSF inflammation and deep gray matter damage in MS involves dysfunction of the blood–cerebrospinal fluid barrier and inflammation in the choroid plexus. Here, we provide a comprehensive review on the role of intrathecal inflammation compartmentalized to CNS and non-neural tissues in progressive MS.

Hydrocephalus is a brain disorder triggered by cerebrospinal fluid accumulation in brain cavities. Even though cerebrospinal fluid flow is known to be driven by the orchestrated beating of the bundled motile cilia of ependymal cells, little is known about the mechanism of ciliary motility. RSPH9 is increasingly becoming recognized as a vital component of radial spokes in ciliary “9 + 2” ultrastructure organization. Here, we show that deletion of the Rsph9 gene leads to the development of hydrocephalus in the early postnatal period. However, the neurodevelopment and astrocyte development are normal in embryonic Rsph9−/− mice. The tubular structure of the central aqueduct was comparable in Rsph9−/− mice. Using high-speed video microscopy, we visualized lower beating amplitude and irregular rotation beating pattern of cilia bundles in Rsph9−/− mice compared with that of wild-type mice. And the centriolar patch size was significantly increased in Rsph9−/− cells. TEM results showed that deletion of Rsph9 causes little impact in ciliary axonemal organization but the Rsph9−/− cilia frequently had abnormal ectopic ciliary membrane inclusions. In addition, hydrocephalus in Rsph9−/− mice results in the development of astrogliosis, microgliosis and cerebrovascular abnormalities. Eventually, the ependymal cells sloughed off of the lateral wall. Our results collectively suggested that RSPH9 is essential for ciliary structure and motility of mouse ependymal cilia, and its deletion causes the pathogenesis of hydrocephalus.

Advances in our understanding of the biological basis and molecular characteristics of ependymal tumors since the latest iteration of the World Health Organization (WHO) classification of CNS tumors (2016) have prompted the cIMPACT-NOW group to recommend a new classification. Separation of ependymal tumors by anatomic site is an important principle of the new classification and was prompted by methylome profiling data to indicate that molecular groups of ependymal tumors in the posterior fossa and supratentorial and spinal compartments are distinct. Common recurrent genetic or epigenetic alterations found in tumors belonging to the main molecular groups have been used to define tumor types at intracranial sites; C11orf95 and YAP1 fusion genes for supratentorial tumors and two types of posterior fossa ependymoma defined by methylation group, PFA and PFB. A recently described type of aggressive spinal ependymoma with MYCN amplification has also been included. Myxopapillary ependymoma and subependymoma have been retained as histopathologically defined tumor types, but the classification has dropped the distinction between classic and anaplastic ependymoma. While the cIMPACT-NOW group considered that data to inform assignment of grade to molecularly defined ependymomas are insufficiently mature, it recommends assigning WHO grade 2 to myxopapillary ependymoma and allows grade 2 or grade 3 to be assigned to ependymomas not defined by molecular status.

Background: Severe intraventricular hemorrhage (IVH) is one of the most devastating neurological complications in preterm infants, with the majority suffering long-term neurological morbidity and up to 50 percent developing post hemorrhagic hydrocephalus (PHH). Despite the importance of this disease, its cytopathological mechanisms are not well known. An in vitro model of IVH is required to investigate the effects of blood and its components on the developing ventricular zone (VZ) and its stem cell niche. To address this need, we developed a new in vitro model to mimic the cytopathological conditions of IVH in the preterm infant. Methods: Maturing neuroepithelial cells from the VZ were harvested from the entire lateral ventricles of wild type C57BL/6 mice at 1-4 days of age and expanded in proliferation media for 3-5 days. At confluence, cells were re-plated onto 24-well plates in differentiation media to generate ependymal cells (EC). At approximately 3-5 days, which corresponded to the onset of ependymal cell differentiation based on the appearance of multiciliated cells , phosphate-buffered saline for controls or syngeneic whole blood for IVH was added to the ependymal cell surface. The cells were examined for the expression of EC markers of differentiation and maturation to qualitatively and quantitatively assess the effect of blood exposure on VZ transition from neuroepithelial cells to EC. Discussion: This model will allow investigators to test cytopathological mechanisms contributing to the pathology of IVH with high temporal resolution and query the impact of injury to the maturation of the VZ. This technique recapitulates features of normal maturation of the VZ in vitro, offering the capacity to investigate the developmental features of VZ biogenesis.

Familial amyloid polyneuropathies (FAPs) are life-threatening, autosomal dominant diseases resulting, in most instances, from transthyretin gene (TTR) variants. A small number of TTR variants lead to leptomeningeal amyloidosis (LA), which is a rare FAP subtype with late-onset central nervous system (CNS) impairment symptoms. Previous studies suggest that LA's CNS selectivity was due to complete endoplasmic reticulum-associated degradation of highly destabilized mutants in peripheral tissues. LA's later age at onset (AAO) was due to lower choroid plexus secretory efficacy. This study reports on a family with LA, including six symptomatic and three presymptomatic members. The LA diagnosis was confirmed by leptomeningeal enhancement on contrast MRI, elevated cerebrospinal fluid protein levels, and positive Congo red staining. The predominant symptoms included headaches, dizziness, vomiting, hallucinations, and cognitive impairments which associated with obstructive hydrocephalus. The TTR p.D38G variant with the lowest secretory efficacy was identified as the genetic cause by whole exome sequencing. The family had a statistically significantly earlier mean AAO of 31.3 ± 7.4 (p = 0.001). These uncommon phenotypes indicate unknown factors influencing the progress of CNS impairment via TTR mutants. Medical imaging examinations suggest the potential early diagnosis value of contrast MRI and the importance of ependyma involvement in LA. LA genetic and clinical data were reviewed and summarized. These findings expand the FAPs' phenotypic spectrum and are valuable in FAP diagnosis, treatment, and further research.

OBJECTIVEVentricular shunts have an unacceptably high failure rate, which approaches 50% of patients at 2 years. Most shunt failures are related to ventricular catheter obstruction. The literature suggests that obstructions are caused by in-growth of choroid plexus and/or reactive cellular aggregation. The authors report endoscopic evidence of overdrainage-related ventricular tissue protrusions (“ependymal bands”) that cause partial or complete obstruction of the ventricular catheter.METHODSA retrospective review was completed on patients undergoing shunt revision surgery between 2008 and 2015, identifying all cases in which the senior author reported endoscopic evidence of ependymal tissue in-growth into ventricular catheters. Detailed clinical, radiological, and surgical findings are described.RESULTSFifty patients underwent 83 endoscopic shunt revision procedures that revealed in-growth of ventricular wall tissue into the catheter tip orifices (ependymal bands), producing partial, complete, or intermittent shunt obstructions. Endoscopic ventricular explorations revealed ependymal bands at various stages of development, which appear to form secondarily to siphoning. Ependymal bands are associated with small ventricles when the shunt is functional, but may dilate at the time of obstruction.CONCLUSIONSVentricular wall protrusions are a significant cause of proximal shunt obstruction, and they appear to be caused by siphoning of surrounding tissue into the ventricular catheter orifices.

Intracranial ependymal cysts are rare neuroepithelial cysts that occur less frequently than arachnoid cysts. The cysts are most often intraparenchymal, but they are rarely reported to be intraventricular. This study evaluates the role of endoscopy in the treatment of intraventricular ependymal cysts (IVECs). Twelve pediatric patients (mean age 4.3 years) with symptomatic IVECs were the subject of this study. The cyst was located inside the lateral ventricle in all cases (100%), it was present in trigone (10 patients, 83.3%), and in temporal horn (2 patients, 16.7%). Concomitant hydrocephalus was present in two patients (16.7%). All patients underwent operations through a purely endoscopic procedure. Communication of the cyst with the subarachnoid space was performed in six patients (50%); endoscopic cystocisternostomy was performed in four patients (33.3%), and endoscopic cystoventriculostomy in two patients (16.7%). Postoperative clinical improvement associated with postoperative reduction in cyst size was encountered in ten patients (83.3%). Improvement of hydrocephalus occurred in both patients who had hydrocephalus (100%). There were no deaths or permanent morbidity. Among the follow-up period (mean 44.3 months), none of the patients required a repeat endoscopic procedure due to recurrence of symptoms or increase in cyst size. Intraventricular ependymal cysts can be effectively treated by endoscopy. Endoscopic fenestration of the cyst wall into subarachnoid space, basal cisterns, or ventricular system can be used in the treatment of these patients with postoperative symptomatic improvement and reduction of cyst size. The procedure is simple, effective, minimally invasive, and associated with low morbidity and mortality rates.

Intraventricular hemorrhage (IVH) is the most common cause of pediatric hydrocephalus in North America but remains poorly understood. Cell junction-mediated ventricular zone (VZ) disruption and astrogliosis are associated with the pathogenesis of congenital, nonhemorrhagic hydrocephalus. Recently, our group demonstrated that VZ disruption is also present in preterm infants with IVH. On the basis of this observation, we hypothesized that blood triggers the loss of VZ cell junction integrity and related cytopathology. In order to test this hypothesis, we developed an in vitro model of IVH by applying syngeneic blood to cultured VZ cells obtained from newborn mice. Following blood treatment, cells were assayed for N-cadherin-dependent adherens junctions, ciliated ependymal cells, and markers of glial activation using immunohistochemistry and immunoblotting. After 24–48 hours of exposure to blood, VZ cell junctions were disrupted as determined by a significant reduction in N-cadherin expression (p

OBJECTIVEThe aim of this work was to investigate the effects of methylprednisolone on the proliferation of endogenous neural stem cells (ENSCs) in nonhuman primates with spinal cord injury (SCI).METHODSA total of 14 healthy cynomolgus monkeys (Macaca fascicularis) (4–5 years of age) were randomly divided into 3 groups: the control group (n = 6), SCI group (n = 6), and methylprednisolone therapy group (n = 2). Only laminectomy was performed in the control animals at T-10. SCI was induced in monkeys using Allen’s weight-drop method (50 mm × 50 g) to injure the posterior portion of the spinal cord at T-10. In the methylprednisolone therapy group, monkeys were intravenously infused with methylprednisolone (30 mg/kg) immediately after SCI. All animals were intravenously infused with 5-bromo-2-deoxyuridine (BrdU) (50 mg/kg/day) for 3 days prior to study end point. The small intestine was dissected for immunohistochemical examination. After 3, 7, and 14 days, the spinal cord segments of the control and SCI groups were dissected to prepare frozen and paraffin sections. The proliferation of ENSCs was evaluated using BrdU and nestin immunofluorescence staining.RESULTSHistological examination showed that a larger number of mucosa epithelial cells in the small intestine of all groups were BrdU positive. Nestin-positive ependymal cells are increased around the central canal after SCI. After 3, 7, and 14 days of SCI, BrdU-positive ependymal cells in the SCI group were significantly increased compared with the control group, and the percentage of BrdU-positive cells in the left/right ventral horns and dorsal horn was significantly higher than that of the control group. Seven days after SCI, the percentages of both BrdU-positive ependymal cells around the central canal and BrdU– and nestin–double positive cells in the left/right ventral horns and dorsal horn were significantly lower in the methylprednisolone therapy group than in the SCI group.CONCLUSIONSWhile ENSCs proliferate significantly after SCI in nonhuman primates, methylprednisolone can inhibit the proliferation of ependymal cells after SCI.

BACKGROUND Aquaporin 4 (AQP4), the most abundant aquaporin in the brain, is a type of bidirectional water channel controlling the brain-water balance and plays a critical role in physiologic and pathologic water balance in the brain. AQP4 was reported to be elevated in hydrocephalus; therefore, we hypothesized that AQP4 contributes to hydrocephalus. In this study, the role of AQP4 in hydrocephalus was explored. MATERIAL AND METHODS The hydrocephalus rat model was established by injection of autologous blood. On Day 1 and Day 3 after injection of autologous blood, magnetic resonance imaging (MRI) and hematoxylin-eosin (HE) staining were performed to detect the changes in ventricles, and quantitative real-time PCR (qRT-PCR) and immunohistochemistry were carried out to detect the changes in AQP4 level. Thereafter, an AQP4-specific siRNA was used to downregulate AQP4. Then, on Day 3 after injection of autologous blood, the levels of AQP4 and connexin-43 were detected by qRT-PCR, immunohistochemistry, immunofluorescence, or Western blot analysis. MRI and HE staining were performed to detect the changes in ventricles, and Evans blue extravasation assay was used to assess blood-brain barrier integrity. RESULTS The hydrocephalus rat model was established successfully, and hydrocephalus rats showed a higher AQP4 level. Silencing AQP4 aggravated the hydrocephalus, with enlarged lateral ventricles and destruction of ependymal integrity and blood-brain barrier. CONCLUSIONS Our study demonstrates that silencing AQP4 aggravates hydrocephalus, indicating that AQP4 protects against hydrocephalus.

Early administration of high-dose steroids and plasma exchange (PE) offers the best chance of treating neuromyelitis optica spectrum disease (NMOSD) attacks, but up to 20% of patients fail to respond. We report the case of a first devastating NMOSD attack leading to death despite optimal treatment. While receiving steroids during a bilateral blinding optic neuritis, this female patient suffered a severe attack involving the spinal cord and circumventricular organs (CVOs), including the pineal gland. Early adjunctive daily PE failed to prevent sudden death. AQP4-antibodies were strongly positive. To our knowledge, this is the first case of exceptionally severe monophasic NMOSD leading to full-blown lesions in all AQP4-expressing sites. Lesions of the periventricular ependyma and CVOs are highly exceptional and the involvement of the pineal gland, which is also a CVO, is novel. Moreover, the patient's condition continued to worsen until death, without any sign of recovery. We term this unexpected outcome the 'anti-Lazarus effect'. Although the mechanisms of resistance to treatment remain elusive, very early initiation of immunosuppressive drugs or adjunctive salvage therapies could be envisioned to manage these devastating attacks.

It has been suggested that urate plays a protective role in neurons, while hyperuricemia is correlated with atherosclerosis and cardiovascular disease. However, whether there is a system that directly transports urate into the brain remains to be clarified. In this study, the localization of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), which are known to be representative reabsorptive urate transporters, was immunohistochemically examined in autopsied human brains. Immunoreactivity of GLUT9 was observed on the apical side of the cytoplasm of epithelial cells in the choroid plexus and in the cilia of ependymal cells of the human brain. Immunoreactivity of URAT1 was observed on the basolateral side of the cytoplasm of epithelial cells in the choroid plexus. In addition, immunoreactivity of GLUT9 and URAT1 was not observed in microvessels of the human brains. The choroid plexus and renal proximal tubule were similar in having a polarized distribution of these two transporters with the two transporters on opposite membranes, but the two transporters' distribution differs between the choroid plexus and the kidney in terms of which membrane (apical/basal) expresses which transporter. These findings support the hypothesis of the direct transport of intravascular urate into the central nervous system through the choroid plexus.

The regenerating tail blastema of lizards appears immunesuppressed, and the distribution of hyaluronate, a possible agent of immunesuppression, is evaluated. Transcriptome data show upregulation of genes stimulating hyaluronate production in the tail and limb blastemas. The distribution of hyaluronate in the tail and limb blastemas has been studied using alcian blue at pH 2.5 and 1.0 and by immunohistochemistry for hyaluronate receptors. Both tail and limb blastemas initially contain hyaluronate, but this glycosaminoglycan disappears in the scarring limb blastema at 25- to 30-day postamputation after intense inflammation. The regenerating tail tip moves distally during regeneration but conserves hyaluronate that is replaced by sulphated glycosaminoglycans and glycoproteins in proximal regions of the regenerating tail. Hyaluronate receptors are diffuse among blastema cells and ependyma of the tail, intense in wound epidermis but low to absent in the scarring limb. The electron microscope shows that an amorphous extracellular matrix likely containing hyaluronate surrounds mesenchymal cells, ependyma and wound epidermis in the tail but is scarce to absent in the limb, whereas collagen fibrils prevail. Extracellular matrix containing hyaluronate may shield blastema cells from circulating immune cells preventing deleterious immune reactions in the tail but not in the limb, a process leading to scarring.

Hydrocephalus is a common congenital anomaly. LCAM1 and MPDZ (MUPP1) are the only known human gene loci associated with non‐syndromic hydrocephalus. To investigate functions of the tight junction‐associated protein Mpdz, we generated mouse models. Global Mpdz gene deletion or conditional inactivation in Nestin‐positive cells led to formation of supratentorial hydrocephalus in the early postnatal period. Blood vessels, epithelial cells of the choroid plexus, and cilia on ependymal cells, which line the ventricular system, remained morphologically intact in Mpdz‐deficient brains. However, flow of cerebrospinal fluid through the cerebral aqueduct was blocked from postnatal day 3 onward. Silencing of Mpdz expression in cultured epithelial cells impaired barrier integrity, and loss of Mpdz in astrocytes increased RhoA activity. In Mpdz‐deficient mice, ependymal cells had morphologically normal tight junctions, but expression of the interacting planar cell polarity protein Pals1 was diminished and barrier integrity got progressively lost. Ependymal denudation was accompanied by reactive astrogliosis leading to aqueductal stenosis. This work provides a relevant hydrocephalus mouse model and demonstrates that Mpdz is essential to maintain integrity of the ependyma.

Drug delivery to the central nervous system (CNS) is complicated by the blood-brain barrier. As a result, many agents that are found to be potentially effective at their site of action cannot be sufficiently or effectively delivered to the CNS and therefore have been discarded and not developed further for clinical use, leaving many CNS diseases untreated. One way to overcome this obstacle is intracerebroventricular (ICV) delivery of the therapeutics directly to cerebrospinal fluid (CSF). Recent experimental and clinical findings reveal that CSF flows from the ventricles throughout the parenchyma towards the subarachnoid space also named minor CSF pathway, while earlier, it was suggested that only in pathological conditions such as hydrocephalus this form of CSF flow occurs. This transependymal flow of CSF provides a route to distribute ICV-infused drugs throughout the brain. More insight on transependymal CSF flow will direct more rational to ICV drug delivery and broaden its clinical indications in managing CNS diseases.

Pathogenic autoantibodies associated with neuromyelitis optica (NMO) induce disease by targeting aquaporin-4 (AQP4) water channels enriched on astrocytic endfeet at blood–brain interfaces. AQP4 is also expressed at cerebrospinal fluid (CSF)–brain interfaces, such as the pial glia limitans and the ependyma and at the choroid plexus blood–CSF barrier. However, little is known regarding pathology at these sites in NMO. Therefore, we evaluated AQP4 expression, microglial reactivity, and complement deposition at pial and ependymal surfaces and in the fourth ventricle choroid plexus in 23 autopsy cases with clinically and/or pathologically confirmed NMO or NMO spectrum disorder. These findings were compared to five cases with multiple sclerosis, five cases of choroid plexus papilloma, and five control cases without central nervous system disease. In the NMO cases, AQP4 immunoreactivity was reduced relative to control levels in the pia (91%; 21/23), ependyma (56%; 9/16), and choroid plexus epithelium (100%; 12/12). AQP4 immunoreactivity was normal in MS cases in these regions. Compared to MS, NMO cases also showed a focal pattern of pial and ependymal complement deposition and more pronounced microglial reactivity. In addition, AQP4 loss, microglial reactivity, and complement deposition colocalized along the pia and ependyma only in NMO cases. Within the choroid plexus, AQP4 loss was coincident with C9neo immunoreactivity on epithelial cell membranes only in NMO cases. These observations demonstrate that NMO immunopathology extends beyond perivascular astrocytic foot processes to include the pia, ependyma, and choroid plexus, suggesting that NMO IgG-induced pathological alterations at CSF–brain and blood–CSF interfaces may contribute to the occurrence of ventriculitis, leptomeningitis, and hydrocephalus observed among NMO patients. Moreover, disruption of the blood–CSF barrier induced by binding of NMO IgG to AQP4 on the basolateral surface of choroid plexus epithelial cells may provide a unique portal for entry of the pathogenic antibody into the central nervous system. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1682-1) contains supplementary material, which is available to authorized users.

We previously found that hematoma worsens hydrocephalus after intraventricular hemorrhage (IVH) via increasing iron deposition and aggravating ependymal cilia injury; therefore, promoting hematoma absorption may be a promising strategy for IVH. Recently, some investigations imply that simvastatin has the ability of accelerating hematoma absorption. Thus, this study was designed to examine the efficacy of simvastatin for IVH in rats. Intracerebral hemorrhage with ventricular extension was induced in adult male Sprague-Dawley rats after autologous blood injection. Simvastatin or vehicle was administered orally at 1 day after IVH and then daily for 1 week. MRI studies were performed to measure the volumes of intracranial hematoma and lateral ventricle at days 1, 3, 7, 14, and 28 after IVH. Motor and neurocognitive functions were assessed at days 1 to 7 and 23 to 28, respectively. Iron deposition, iron-related protein expression, ependymal damage, and histology were detected at day 28. Expression of CD36 scavenger receptor (facilitating phagocytosis) was examined at day 3 after IVH using western blotting and immunofluorescence. Simvastatin significantly increased hematoma absorption ratio, reduced ventricular volume, and attenuated neurological dysfunction post-IVH. In addition, less iron accumulation and more cilia survival was observed in the simvastatin group when compared with the control. What's more, higher expression of CD36 was detected around the hematoma after simvastatin administration. Simvastatin significantly enhanced brain hematoma absorption, alleviated hydrocephalus, and improved neurological recovery after experimental IVH, which may in part by upregulating CD36 expression. Our data suggest that early simvastatin use may be a novel therapy for IVH patients.

Fluorescence in the ventricular wall or the ependyma during fluorescence-guided resection (FGR) of malignant glioma is commonly observed when malignant gliomas infiltrate the ventricles. However, the underlying pathophysiology and clinical importance are largely unknown but may play a role in deciding whether to continue resection into the ventricles or not. Here, we systematically review available data regarding ependymal fluorescence in FGR using five aminolevulinic acid (5-ALA) and sodium fluorescein (SF). A literature search on MEDLINE, EMBASE, and WEB OF SCIENCE was performed using the following headings and search operators: ependy* fluorescence AND (5-ALA OR five aminolevulinic acid), ventric* wall fluorescence AND (5-ALA OR five aminolevulinic acid), ependy* fluorescence AND fluorescein, and ventric* wall fluorescence AND fluorescein. Both authors analyzed abstracts independently. Included articles were further reviewed for prevalence of ependymal fluorescence, patterns of fluorescence, and histopathological characteristics of sampled tissues as well as radiological signs of ependymal fluorescence. Results are reported according to the PRISMA statement. Of 202 records identified, 6 studies were included compiling a total number of 198 patients treated with FGR using 5-ALA. No study on ependymal fluorescence after administration of SF was found. Overall prevalence of ependymal fluorescence was 61.4%. A total of 54.5% of cases were found to be positive for tumor cells. A total of 25.5% of patients with ependymal fluorescence were related to contrast enhancement in ventricular walls. The phenomenon of ventricular wall fluorescence in 5-ALA-derived fluorescence-guided resection of malignant glioma is poorly understood and not always may fluorescence represent tumor infiltration. A larger scale prospective sampling study with molecular analyses is currently ongoing and will hopefully provide further insight into pathophysiology and clinical implications of ependymal fluorescence.

Hydrocephalus is a rare and devastating complication of mumps encephalitis. The histopathological correlates of mumps infection in central nervous system tissues are not well-characterized. We present the case of a 54-year-old patient who suffered long-term neuropsychiatric sequelae and hydrocephalus as a consequence of a childhood mumps infection. Brain autopsy revealed significant dilation of the lateral and third ventricles. Aqueductal stenosis was not observed on premortem imaging or on gross examination. Histology revealed loss of ependymal epithelium throughout the aqueduct and ventricular system. Macrophage conglomerates were identified within the cerebral aqueduct at the level of the pons in addition to subjacent periaqueductal gliosis and scattered Rosenthal fibers. Together, these findings support primary ependymal injury as a pathophysiological mechanism in the development of chronic hydrocephalus following mumps infection. Finally, we review the existing literature and discuss potential mechanisms of disease.

Ependymal cells (EpCs) are a kind of multi-potent stem cells in the central canal of adult spinal cord, which proliferate following spinal cord injury (SCI). Although they can differentiate into functional neurons

Stem cells have a high therapeutic potential for the treatment of spinal cord injury (SCI). We have shown previously that endogenous stem cell potential is confined to ependymal cells in the adult spinal cord which could be targeted for non-invasive SCI therapy. However, ependymal cells are an understudied cell population. Taking advantage of transgenic lines, we characterize the appearance and potential of ependymal cells during development. We show that spinal cord stem cell potential in vitro is contained within these cells by birth. Moreover, juvenile cultures generate more neurospheres and more oligodendrocytes than adult ones. Interestingly, juvenile ependymal cells in vivo contribute to glial scar formation after severe but not mild SCI, due to a more effective sealing of the lesion by other glial cells. This study highlights the importance of the age-dependent potential of stem cells and post-SCI environment in order to utilize ependymal cell's regenerative potential., Graphical Abstract Schematic representation of different cell type responses to spinal cord injury (SCI) in juvenile and adult mice. In vitro juvenile ependymal cells have higher intrinsic self-renewal capacity with or without SCI compared to adults. After differentiation, juvenile ependymal cells can generate more oligodendrocytes than adult ones before or after SCI. In vivo juvenile spinal cord shows better recovery by sealing the lesion more efficiently: more dense astrocytic interaction, less astrogliosis, less infiltrating pericytes, microglia and blood-derived macrophages. After SCI, ependymal cells do not get activated in juvenile mild lesion due to the higher self-repair efficiency, while they are required for wound healing in mature adults or after a more severe lesion in juveniles. Thus, the activation of ependymal cells depends on age and lesion size despite their higher intrinsic stem cell potential at the juvenile stage. This study suggests that juvenile animals have higher self-repair efficiency and spinal cord environment and age should be taken into consideration to design further therapies. P21 = postnatal day 21, DFT = dorsal funiculi transection, DH = dorsal hemisection.Image 1, Highlights • All spinal cord stem cell potential is contained within ependymal cells by birth but decreases over time. • Recruitment of ependymal cells after injury is age- and lesion-dependent. • Juvenile endogenous spinal cord glial cells better seal the lesion than in adults. Spinal cord (SC) injury is an incurable condition. It leads to permanent paralysis and loss of sensation. Many cell therapies have been tested for treatment but limitations remain due to limited knowledge of the SC following injury. We used transgenic mice to study young and mature SC after injury. We found that the SC stem cells, a cell type that can generate other cells for recovery, are present from postnatal stage. Furthermore, we discovered that these stem cells are recruited differently in an age- and lesion-dependent matter affecting their repair potential. This has important implications for further design of therapies.

According to previous opinion, the derivation of neurons and glia from the central canal (CC) lining of the spinal cord in rodents should occur in the embryonic period. Reports of the mitotic activity observed in the lining during postnatal development have often been contradictory, and proliferation was ascribed to the generation of ependymocytes, which are necessary for the elongation of CC walls. Our study quantifies the intensity of proliferation and determines the cellularity of the CC lining in reference to lumbar spinal segment L4 during the postnatal development of rats. The presence of dividing cells peaks in the CC lining on postnatal day 8 (P8), with division occurring in 19.2% ± 3.2% of cells. In adult rats, 3.6% ± 0.9% of cells still proliferate, whereas, in mice, 10.3% ± 2.3% of cells at P8 and only 0.6% ± 0.2% of cells in the CC lining in adulthood are proliferating. In the rat, the length of the cell cycle increases from 100.3 ± 35.7 hours at P1 to 401.4 ± 80.6 hours at P43, with a sudden extension between P15 and P22. Despite the intensive proliferation, the total cellularity of the CC lining at the L4 spinal segment significantly descended in from P8 to P15. According to our calculations, the estimated cellularity was significantly higher compared with the measured cellularity of the CC lining at P15. Our results indicate that CC lining serves as a source of cells beyond ependymal cells during the first postnatal weeks of the rat. J. Comp. Neurol. 525:693-707, 2017. © 2016 Wiley Periodicals, Inc.

Chordoid glioma (CG) is a World Health Organization classified grade II tumor located exclusively in the region of anterior third ventricle. Association of CG with other lesions is extremely rare. We report a case of CG in a 45-year-old male coexisting with an epidermoid cyst in the third ventricle. Ultrastructural examination of the CG revealed microvilli, junctional complexes, and intermediate filaments within the cytoplasm suggesting origin from specialized ependyma. The association of the 2 lesions appears coincidental as convincing evidence for a common histogenesis was not found.

Idiopathic basal ganglia calcification is a brain calcification disorder that has been genetically linked to autosomal dominant mutations in the sodium-dependent phosphate co-transporter, SLC20A2. The mechanisms whereby deficiency of Slc20a2 leads to basal ganglion calcification are unknown. In the mouse brain, we found that Slc20a2 was expressed in tissues that produce and/or regulate cerebrospinal fluid, including choroid plexus, ependyma and arteriolar smooth muscle cells. Haploinsufficient Slc20a2 +/- mice developed age-dependent basal ganglia calcification that formed in glymphatic pathway-associated arterioles. Slc20a2 deficiency uncovered phosphate homeostasis dysregulation characterized by abnormally high cerebrospinal fluid phosphate levels and hydrocephalus, in addition to basal ganglia calcification. Slc20a2 siRNA knockdown in smooth muscle cells revealed increased susceptibility to high phosphate-induced calcification. These data suggested that loss of Slc20a2 led to dysregulated phosphate homeostasis and enhanced susceptibility of arteriolar smooth muscle cells to elevated phosphate-induced calcification. Together, dysregulated cerebrospinal fluid phosphate and enhanced smooth muscle cell susceptibility may predispose to glymphatic pathway-associated arteriolar calcification.

Well-differentiated human cancers share transcriptional programmes with the normal tissue counterparts from which they arise. These programmes broadly influence cell behaviour and function and are integral modulators of malignancy. Here, we show that the master regulator of motile ciliogenesis, FOXJ1, is highly expressed in cells along the ventricular surface of the human brain. Strong expression is present in cells of the ependyma and the choroid plexus as well as in a subset of cells residing in the subventricular zone. Expression of FOXJ1 and its transcriptional programme is maintained in many well-differentiated human tumours that arise along the ventricle, including low-grade ependymal tumours and choroid plexus papillomas. Anaplastic ependymomas as well as choroid plexus carcinomas show decreased FOXJ1 expression and its associated ciliogenesis programme genes. In ependymomas and choroid plexus tumours, reduced expression of FOXJ1 and its ciliogenesis programme are markers of poor outcome and are therefore useful biomarkers for assessing these tumours. Transitions in ciliogenesis define distinct differentiation states in ependymal and choroid plexus tumours with important implications for patient care. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

OBJECT Periventricular lucency (PVL) is often observed in the hydrocephalic brain on CT or MRI. Earlier studies have proposed the extravasation of ventricular CSF into the periventricular white matter or transependymal CSF absorption as possible causes of PVL in hydrocephalus. However, there is insufficient evidence for either theory to be conclusive. METHODS A finite element (FE) model of the hydrocephalic brain with detailed anatomical geometry was constructed to investigate the possible mechanism of PVL in hydrocephalus. The initiation of hydrocephalus was modeled by applying a transmantle pressure gradient (TPG). The model was exposed to varying TPGs to investigate the effects of different geometrical characteristics on the distribution of PVL. The edema map was derived based on the interstitial pore pressure. RESULTS The model simulated the main radiological features of hydrocephalus, i.e., ventriculomegaly and PVL. The degree of PVL, assessed by the pore pressure, was prominent in mild to moderate ventriculomegaly. As the degree of ventriculomegaly exceeded certain values, the pore pressure across the cerebrum became positive, thus inducing the disappearance of PVL. CONCLUSIONS The results are in accordance with common clinical findings of PVL. The degree of ventriculomegaly significantly influences the development of PVL, but two factors were not linearly correlated. The results are indicative of the transependymal CSF absorption as a possible cause of PVL, but the extravasation theory cannot be formally rejected.

Ependymal cells are epithelial support cells that line the central canal and ventricular cavities of the central nervous system, providing the interface between the cerebrospinal fluid and the parenchyma of the brain and spinal cord. The spinal ependymal layer (SEL) is composed of 3 main cell types: tanycytes, ependymocytes, and cerebrospinal fluid–contacting neurons. A fourth cell type, termed the supraependymal cell, is also occasionally described. Cells of the SEL show restricted proliferative capacity in health but display neural stem cell properties both in vitro and in vivo in various disease states. A growing body of literature is devoted to the regenerative roles of the SEL, particularly in the context of spinal cord injury, where mechanical damage to the spinal cord leads to a significant increase in SEL proliferation. SEL-derived cell progeny migrate to sites of injury within the injured spinal cord parenchyma and contribute primarily to glial scar formation. In additional to their role as endogenous neural stem cells, cells of the SEL may be an important source of cytokines and other cell signaling molecules, such as tumor necrosis factor, heat shock proteins, and various growth factors. The SEL has become of recent interest to neuroscience researchers because of its potential to participate in and respond to diseases affecting the spinal cord (eg, traumatic spinal cord injury) and neurodegenerative disease. The intimate association of the SEL with the cerebrospinal fluid makes intrathecal therapies a viable option, and recent studies highlight the potential promise of treatments that augment SEL responses to disease.

Many pregnant women and prematurely born infants require medication for clinical conditions including cancer, cardiac defects and psychiatric disorders. In adults drug transfer from blood into brain is mostly restricted by efflux mechanisms (ATP-binding cassette, ABC transporters). These mechanisms have been little studied during brain development. Here expression of eight ABC transporters (abcb1a, abcb1b, abcg2, abcc1, abcc2, abcc3, abcc4, abcc5) and activity of conjugating enzyme glutathione-s-transferase (GST) were measured in livers, brain cortices (blood-brain-barrier) and choroid plexuses (blood-cerebrospinal fluid, CSF, barrier) during postnatal rat development. Controls were compared to animals chronically injected (4 days, 200 mg/kg/day) with known abcb1a inducer diallyl sulfide (DAS). Results reveal both tissue- and age-dependent regulation. In liver abcb1a and abcc3 were up-regulated at all ages. In cortex abcb1a/b, abcg2 and abcc4/abcc5 were up-regulated in adults only, while in choroid plexus abcb1a and abcc2 were up-regulated only at P14. DAS treatment increased GST activity in livers, but not in cortex or choroid plexuses. Immunocytochemistry of ABC transporters at the CSF-brain interface showed that PGP and BCRP predominated in neuroepithelium while MRP2/4/5 were prominent in adult ependyma. These results indicate an age-related capacity of brain barriers to dynamically regulate their defence mechanisms when chronically challenged by xenobiotic compounds.

The cerebrospinal fluid (CSF) performs key functions for the developing central nervous system and for the adult brain. It is, indeed, a complex molecular private milieu of the brain clearing a series of compounds and conveying a wealth of signal molecules. The flow of the CSF throughout the ventricular system involves two different mechanisms: the bulk flow, driven by arterio-venous pressure gradients and arterial pulsations, and the laminar flow, driven by cilia beating of ependymal cells. Disruption of normal CSF circulation and turnover contributes to the development of many diseases. This review is aimed to bring into discussion early and new evidence concerning the brain development, ependymogenesis, and the probable mechanisms by which abnormalities in the ependymogenesis program may lead to both foetal onset hydrocephalus and abnormal neurogenesis. Evidence strongly suggests that several genetic mutations and certain foreign signals all convey into a final common pathway leading to a cell junction pathology of cells lining the ventricular walls (ventricular zone, VZ). The early disruption of the VZ of the embryonic telencephalon implies the loss of neural stem cells (NSC) and abnormal neurogenesis, while the disruption of the VZ of the Sylvius aqueduct during the perinatal period results in the loss of multiciliated ependyma, aqueduct stenosis/obliteration, alteration of the laminar, and bulk flow of CSF and hydrocephalus. These findings establish the bases for the transplantation of NSC into the ventricles of foetuses developing hydrocephalus to diminish/repair the outcomes of VZ disruption.

Introduction The area postrema in the caudal fourth ventricular floor is highly vascular without blood-brain or blood-cerebrospinal fluid barrier. In addition to its function as vomiting center, several others are part of the circumventricular organs for vasomotor/angiotensin II regulation, role in neuromyelitis optica related to aquaporin-4, and somatic growth and appetite regulation. Functions are immature at birth. The purpose was to demonstrate neuronal, synaptic, glial, or ependymal maturation in the area postrema of normal fetuses. We describe three area postrema tumors. Methods Sections of caudal fourth ventricle of 12 normal human fetal brains at autopsy aged six to 40 weeks and three infants aged three to 18 months were examined. Immunocytochemical neuronal and glial markers were applied to paraffin sections. Two infants with area postrema tumors and another with neurocutaneous melanocytosis and pernicious vomiting also studied. Results Area postrema neurons exhibited cytologic maturity and synaptic circuitry by 14 weeks'. Astrocytes coexpressed vimentin, glial fibrillary acidic protein, and S-100β protein. The ependyma is thin over area postrema, with fetal ependymocytic basal processes. A glial layer separates area postrema from medullary tegmentum. Melanocytes infiltrated area postrema in the toddler with pernicious vomiting; two children had primary area postrema pilocytic astrocytomas. Conclusions Although area postrema is cytologically mature by 14 weeks, growth increases and functions mature during postnatal months. We recommend neuroimaging for patients with unexplained vomiting and that area postrema neuropathology includes synaptophysin and microtubule-associated protein-2 in patients with suspected dysfunction.

Light and electron microscope studies indicate that the old ependyma just proximal to the plane of amputation in early lizard tail regenerates shows a sequence of morphological changes which suggests that it as well as the new ependyma growing into the regenerate may play an active role in the initiation and maintenance of early tail regeneration. The old ependyma close to the plane of amputation undergoes hypertrophy and/or hyperplasia causing a partial closure of the central canal and pseudostratification. Its nuclei shift from an original apical position to a basal one. The ependymal processes become more prominent and extend to the pia, a condition not found more rostrally. There is also a significant increase in the amount of Golgi substance and a moderate increase in the rough endoplasmic reticulum. These observations lead to the thought that these cellular changes may be an expression of enhanced secretion and other activities in the old and new ependyma just proximal or distal to the plane of amputation.