Hydrocephalic Brain Research Articles

Stereotactic anatomy of the third ventricle

PurposeEndoscopic third ventriculostomy (ETV) is a surgical procedure that can lead to complications and requires detailed preoperative planning. This study aimed to provide a more accurate understanding of the anatomy of the third ventricle and the location of important structures to improve the safety and success of ETV.MethodsWe measured the stereotactic coordinates of six points of interest relative to a predefined stereotactic reference point in 23 cadaver brain hemi-sections, 200 normal brain magnetic resonance imaging (MRI) scans, and 24 hydrocephalic brain MRI scans. The measurements were statistically analyzed, and comparisons were made.ResultsWe found some statistically significant differences between genders in MRIs from healthy subjects. We also found statistically significant differences between MRIs from healthy subjects and both cadaver brains and MRIs with hydrocephalus, though their magnitude is very small and not clinically relevant. Some stereotactic points were more posteriorly and inferiorly located in cadaver brains, particularly the infundibular recess and the basilar artery. It was found that all stereotactic points studied were more posteriorly located in brains with hydrocephalus.ConclusionThe study describes periventricular structures in cadaver brains and MRI scans from healthy and hydrocephalic subjects, which can guide neurosurgeons in planning surgical approaches to the third ventricle. Overall, the study contributes to understanding ETV and provides insights for improving its safety and efficacy. The findings also support that practicing on cadaveric brains can still provide valuable information and is valid for study and training of neurosurgeons unfamiliar with the ETV technique.

Early postnatal microglial ablation in the Ccdc39 mouse model reveals adverse effects on brain development and in neonatal hydrocephalus

BackgroundNeonatal hydrocephalus is a congenital abnormality resulting in an inflammatory response and microglial cell activation both clinically and in animal models. Previously, we reported a mutation in a motile cilia gene, Ccdc39 that develops neonatal progressive hydrocephalus (prh) with inflammatory microglia. We discovered significantly increased amoeboid-shaped activated microglia in periventricular white matter edema, reduced mature homeostatic microglia in grey matter, and reduced myelination in the prh model. Recently, the role of microglia in animal models of adult brain disorders was examined using cell type-specific ablation by colony-stimulating factor-1 receptor (CSF1R) inhibitor, however, little information exists regarding the role of microglia in neonatal brain disorders such as hydrocephalus. Therefore, we aim to see if ablating pro-inflammatory microglia, and thus suppressing the inflammatory response, in a neonatal hydrocephalic mouse line could have beneficial effects.MethodsIn this study, Plexxikon 5622 (PLX5622), a CSF1R inhibitor, was subcutaneously administered to wild-type (WT) and prh mutant mice daily from postnatal day (P) 3 to P7. MRI-estimated brain volume was compared with untreated WT and prh mutants P7-9 and immunohistochemistry of the brain sections was performed at P8 and P18-21.ResultsPLX5622 injections successfully ablated IBA1-positive microglia in both the WT and prh mutants at P8. Of the microglia that are resistant to PLX5622 treatment, there was a higher percentage of amoeboid-shaped microglia, identified by morphology with retracted processes. In PLX-treated prh mutants, there was increased ventriculomegaly and no change in the total brain volume was observed. Also, the PLX5622 treatment significantly reduced myelination in WT mice at P8, although this was recovered after full microglia repopulation by P20. Microglia repopulation in the mutants worsened hypomyelination at P20.ConclusionsMicroglia ablation in the neonatal hydrocephalic brain does not improve white matter edema, and actually worsens ventricular enlargement and hypomyelination, suggesting critical functions of homeostatic ramified microglia to better improve brain development with neonatal hydrocephalus. Future studies with detailed examination of microglial development and status may provide a clarification of the need for microglia in neonatal brain development.

"Floppy brain" in congenital hydrocephalus.

Hydrocephalus is classically considered to be a disorder of altered cerebrospinal fluid (CSF) circulation, leading to the dilation of cerebral ventricles. Here, we report a clinical case of a patient who presented with fetal-onset hydrocephalus with diffusely reduced cortical and white matter volumes resulting from a genetic mutation in L1CAM, a well-known hydrocephalus disease gene involved in neuronal cell adhesion and axon development. After CSF was drained from the ventricle intraoperatively, the patient's cortical mantle collapsed and exhibited a "floppy" appearance on neuroimaging, suggesting an inability of the hydrocephalic brain to maintain its structural integrity. The case provides clinical support for altered brain biomechanical properties in human hydrocephalus and adds to the emerging hypothesis that altered brain development with secondary impact on brain structural stability may contribute to ventricular enlargement in some subsets of hydrocephalus.

Long-term recovery behavior of brain tissue in hydrocephalus patients after shunting

The unpredictable complexities in hydrocephalus shunt outcomes may be related to the recovery behavior of brain tissue after shunting. The simulated cerebrospinal fluid (CSF) velocity and intracranial pressure (ICP) over 15 months after shunting were validated by experimental data. The mean strain and creep of the brain had notable changes after shunting and their trends were monotonic. The highest stiffness of the hydrocephalic brain was in the first consolidation phase (between pre-shunting to 1 month after shunting). The viscous component overcame and damped the input load in the third consolidation phase (after the fifteenth month) and changes in brain volume were stopped. The long-intracranial elastance (long-IE) changed oscillatory after shunting and there was not a linear relationship between long-IE and ICP. We showed the long-term effect of the viscous component on brain recovery behavior of hydrocephalic brain. The results shed light on the brain recovery mechanism after shunting and the mechanisms for shunt failure.

A review on Tsukushi: mammalian development, disorders, and therapy.

Tsukushi (TSK), a leucine-rich peptidoglycan in the extracellular compartment, mediates multiple signaling pathways that are critical for development and metabolism. TSK regulates signaling pathways that eventually control cellular communication, proliferation, and cell fate determination. Research on TSK has become more sophisticated in recent years, illustrating its involvement in the physiology and pathophysiology of neural, genetic, and metabolic diseases. In a recent study, we showed that TSK therapy reversed the pathophysiological abnormalities of the hydrocephalic (a neurological disorder) brain in mice. This review summarizes the roles of TSK in key signaling processes in the mammalian development, disorders, and evaluating its possible therapeutic and diagnostic potential.

Cerebral Blood Perfusion is Improved Regionally After Shunt Surgery in the High-Pressure Hydrocephalic Brain.

To show the abnormal cerebral hemodynamics, in high-pressure hydrocephalic patients, could be restored by shunt surgery, and the tympanic membrane temperature (TMT) could be used to non-invasively monitor this recovery process. One-hundred-and-four patients, with high-pressure hydrocephalus (spinal tap opening pressure > 180 mmH2O), were prospectively enrolled in our study. The computed tomography perfusion (CTP) was scheduled for 7-10 days preand post-shunt surgery. The TMT and Glasgow Coma Scale (GCS) scores were collected during the same session. The CTP after the shunt surgery revealed a significant increase in cerebral blood volume (CBV) in both hemispheres (p < 0.05). More specifically, this CBV increase was observed in the midbrain, cerebellum, basal ganglion, temporal lobe, and frontal lobe regions (all p < 0.05). Simultaneously, patients' post-surgical TMT and GCS scores also increased compared to their pre-surgical scores since the first post-shunt follow-up (p < 0.01). Notably, while the GCS scores continued to increase during the post-shunt follow-up, the TMT exhibited a fluctuation period after the shunt and required seven days to reach a steady state. Our study revealed that a shunt could significantly increase cerebral perfusion in high-pressure hydrocephalic patients in a region-specific manner. During the perioperative period of hydrocephalus, TMT can be used to monitor cerebral hemodynamic changes.

Cotton rats (Sigmodon hispidus) with a high prevalence of hydrocephalus without clinical symptoms.

Normal-pressure hydrocephalus (NPH) is a condition in which the ventricle is enlarged without elevated cerebrospinal fluid pressure, and it generally develops in later life and progresses slowly. A complete animal model that mimics human idiopathic NPH has not yet been established, and the onset mechanisms and detailed pathomechanisms of NPH are not fully understood. Here, we demonstrate a high spontaneous prevalence (34.6%) of hydrocephalus without clinical symptoms in inbred cotton rats (Sigmodon hispidus). In all 46 hydrocephalic cotton rats, the severity was mild or moderate and not severe. The dilation was limited to the lateral ventricles, and none of the hemorrhage, ventriculitis, meningitis, or tumor formation was found in hydrocephalic cotton rats. These findings indicate that the type of hydrocephalus in cotton rats is similar to that of communicating idiopathic NPH. Histopathological examinations revealed that the inner granular and pyramidal layers (layers IV and V) of the neocortex became thinner in hydrocephalic brains. A small number of pyramidal cells were positive for Fluoro-Jade C (a degenerating neuron marker) and ionized calcium-binding adaptor molecule 1 (Iba1)-immunoreactive microglia were in contact with the degenerating neurons in the hydrocephalic neocortex, suggesting that hydrocephalic cotton rats are more or less impaired projections from the neocortex. This study highlights cotton rats as a candidate for novel models to elucidate the pathomechanism of idiopathic NPH. Additionally, cotton rats have some noticeable systemic pathological phenotypes, such as chronic kidney disease and metabolic disorders. Thus, this model might also be useful for researching the comorbidities of NPH to other diseases.

Fetal and Perinatal Brain Autopsy: Useful Macroscopic Techniques Including Agar In-situ and Pre-Embedding Methods.

Fragile perinatal and fetal brains are the rule rather than the exception for developmental neuropathologists. Retrieving the fresh brain from the skull and examining early fetal, macerated or severely hydrocephalic brains after fixation can be a challenge. Textbooks on neurodevelopmental pathology mention these challenges to macroscopic examination of the developing central nervous system only in passing, but many perinatal pathologists recognize this diagnostic problem. We reviewed protocols and publications on the removal, fixation, slicing and sampling of these fetal- and perinatal brains. In addition, we describe a technique to facilitate the removal of severely hydrocephalic brains with very thin cerebral walls from the skull by replacing the intraventricular fluid with agar in-situ. Furthermore, we present a method for post-fixation pre-embedding in agar to facilitate slicing, macroscopic examination and sampling of fragile and macerated brains.

Inference of Diagnostic Markers and Therapeutic Targets From CSF Proteomics for the Treatment of Hydrocephalus.

The purpose of this mini-review is to examine if publicly available cerebrospinal fluid (CSF) proteomics data sets can be exploited to provide insight into the etiology of hydrocephalus, into the character of the injury inflicted on the parenchyma by ventriculomegaly, and into the response of the brain to this condition. While this undertaking was instigated by reanalysis of recent comparative proteomics of CSF collected from the brain of healthy and Mpdz knockout (KO) mice (Yang et al. 2019), it is an opportunity to survey previously published CSF proteomics data sets to determine if they can be pooled together to that end. The overabundance of extracellular matrix (ECM) proteins, complement factors, and apolipoproteins in the CSF of Mpdz KO mice was taken to indicate that the hydrocephalic brain underwent ischemia, inflammation, and demyelination. The overabundance of five cytokine-binding proteins could be linked uniquely to insulin-like growth factor (IGF) secretion and signaling. The overabundance of two serpins, angiotensinogen and pigment epithelium-derived factor (PEDF) was considered as a biomarker of anti-angiogenic negative-feedback mechanisms to reduce CSF production. These findings raise the intriguing propositions that CSF proteomics can identify biomarkers of case-specific injuries, and that IGF signaling and angiogenesis pathways can serve as therapeutic targets. It appears, however, that the currently available proteomics data is not amenable to comparison of CSF from normal and hydrocephalic patients and cannot be used test the premise of those propositions.

Radiological, biomechanical and histopathological characteristics of rat brain in Kaolin-induced hydrocephalus

Objective: A better understanding of the pathophysiology and underlying mechanisms of brain damage in hydrocephalus is vital in developing diagnostic, observational and treatment tools that will have an impact on hydrocephalus outcomes. In this study, we aimed to demonstrate the radiological, biomechanical and histopathological characteristics of rat brain tissue in an experimental hydrocephalus model.&#x0D; Materials and Methods: Thirty-six male Sprague-Dawley rats (21 days old, weighing between 150 and 200 grams) were used in this study. Animals were randomly assigned to control (n = 6), 1-week hydrocephalus (n = 10), 2-week hydrocephalus (n = 10) and 3-week hydrocephalus (n = 10) groups. Hydrocephalus was induced with cisternal kaolin injection and controls received sham injection. Magnetic resonance imaging was used to measure ventricle size and cortical thickness. Vital signs, cerebral blood flow (CBF), mechanical tests and brain histology were assessed.&#x0D; Results: Three rats in the hydrocephalus group died during the follow-up, yielding an overall mortality of 10% among animals from hydrocephalus groups. Ventricular width, cross-sectional area of the lateral ventricles, ventricular index and ventricle / brain area ratio progressively increased and cortical thickness progressively decreased following kaolin injection. CBF was significantly lower at baseline than at 1st, 2nd and 3rd week (p &lt; 0.05, for all). ICP was significantly elevated in all hydrocephalic groups in comparison with controls. EIT that was calculated from the first load-unload indentation test showed a significant increase at 2nd week post-injection (p=0.0001), indicating increased intracranial stiffness. However, this significant difference disappeared at 3rd week (p=0.956). Quantitative immunohistochemistry showed that hydrocephalic brains demonstrated significantly less NeuN-positive cells and significantly higher IBA-1-positive microglia and glial fibrillary acidic protein positive astrocytes cells in the cortex.&#x0D; Discussion and Conclusion: Cisternal kaolin injection causes varying degrees of ventricular enlargement in a rat model and hydrocephalus might contribute to neuronal and axonal damage and alter brain stiffness through axonal stretching or local hypoperfusion progressively over a period of days to months. As shown in this study, irreversible changes in viscoelastic behaviour and cellular structure develop in the late stages of hydrocephalus, suggesting the importance of early intervention in the treatment of hydrocephalus.

Altered folate binding protein expression and folate delivery are associated with congenital hydrocephalus in the hydrocephalic Texas rat

Hydrocephalus (HC) is an imbalance in cerebrospinal fluid (CSF) secretion/absorption resulting in fluid accumulation within the brain with consequential pathophysiology. Our research has identified a unique cerebral folate system in which depletion of CSF 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is associated with cortical progenitor cell-cycle arrest in hydrocephalic Texas (H-Tx) rats. We used tissue culture, immunohistochemistry, in-situ PCR and RT-PCR and found that the in-vitro proliferation of arachnoid cells is highly folate-dependent with exacerbated proliferation occurring in hydrocephalic CSF that has low FDH but high folate-receptor-alpha (FRα) and folate. Adding FDH to this CSF prevented aberrant proliferation indicating a regulatory function of FDH on CSF folate concentration. Arachnoid cells have no detectable mRNA for FRα or FDH, but FDH mRNA is found in the choroid plexus (CP) and CSF microvesicles. Co-localization of FDH, FRα and folate suggests important functions of FDH in cerebral folate transport, buffering and function. In conclusion, abnormal CSF levels of FDH, FRα and folate inhibit cortical cell proliferation but allow uncontrolled arachnoid cell division that should increase fluid absorption by increasing the arachnoid although this fails in the hydrocephalic brain. FDH appears to buffer available folate to control arachnoid proliferation and function.

Hydrocephalus-Induced Changes in the Endocrine Hypothalamus of the Hamster

Hydroceplanllus-induced changes in intracranial pressure (ICP), ventricular size, periventricular edema and erytlirocyte density(ED), median eminence thickness, and pituitary gland morphology were determined in adult female hamsters (Mesocricetus auratus). Hydrocephalus (HC) was induced by intracisternal injection of kaolin (0.03 ml, 50 mg/ml saline); controls did not receive kaolin. Animais were chronically cannulated and ICP measured periodically (Camino V 420). At selecied times control and treated animals were decapitated, brains removed with the pituitary gland attached and fixed by immersion in formalin. Coronal brain slices containing the paraventricular nuclei (PVN), supraoptic nuclei (SON), suprachiosmatic nuclei (SCN), subfornical organ (SFO) and median eminence (ME) were prepared using a rodent brain matrix slicer and ventricular arca was quantitated by morphometric analysis (Jandel Video Analysis System). Samples were collected from the cortex and periventricular white matter (containing the PVN, SON, and SCN) and the median eminence. The whole pituitary gland was also collected for determination of specific gravity by linear density column method. Erythrocyte Densiry was assessed by immersing hydrocephalic brain slices containing the select nuclei in Karnoviskys fixative on day 9 post HC induction, and in simerythrocytes stained for endogenous peroxidase by tretramethyl benzidine cylochemistry to facilitate visualization. Previous studies in our laboratory have establislied that HC can result in alterations in estrous cycle, water balance, food intake and growth. The result in part from decrease perfusion of the endocrine liypothalamus and pituitary gland, edema and pressure-induced changes in the median eminence structures.

Neuropathological Changes in Hydrocephalus—A Comprehensive Review

Hydrocephalus is a heterogeneous, neurological condition characterized by altered flow of cerebrospinal fluid (CSF) that can occur at any age. Neuropathological changes associated with hydrocephalus are dependent on the age of onset, rate of ventricular enlargement, and the etiology. Hydrocephalic brain damage is also influenced by contributions from both mechanical forces and metabolic changes, which increases the heterogeneity of the condition. However, as ventriculomegaly progresses, the surrounding brain tissue is compressed within the cranial vault, elevating intracranial pressure and eventually leading to severe brain damage. From this perspective, it makes sense that periventricular brain regions are the initial sites of damage as ventricular dilatation occurs. The following review of neuropathological changes in hydrocephalus will first discuss cellular and region specific damage from the ventricles and outward towards the cortex and brainstem. This will be followed by vascular and hypoxic changes associated with the condition. Both types of brain impairments are dependent on the severity of the condition, and they will be described accordingly.

Characterization of spontaneous hydrocephalus development in the young atherosclerosis-prone mice.

Little has been reported on whether abnormal lipid metabolism affects hydrocephalus, although congenital malformations and infectious diseases are major causal factors for hydrocephalus development. In a study on the pathogenesis of atherogenesis in mice, we unexpectedly discovered that hydrocephalus occurred in partial apolipoptotein E (apoE) and low-density lipoprotein receptor (LDLR) double-knockout (apoE/LDLR) mice fed either chow or a high-fat and high-cholesterol diet between the ages of 4 and 12 weeks. In the 12-week-old high-fat and high-cholesterol group, the incidence rate was as high as 15%. Transcription levels of transforming growth factor-β1 (TGF-β1), Smad3, Smad4, and Smad7 in the cortex of the hydrocephalic cerebrum were significant downregulated in 4-week-old mice, but were increased in the 8 and 12-week-old groups compared with that of age-matched nonhydrocephalic mice. The mRNA level of tissue inhibitor of metalloproteinases 1 was significantly increased, whereas matrix metalloproteinase-9 was lower in hydrocephalic mice of all ages. The translation level of TGF-β1 increased in the hydrocephalic brains of 8 and 12-week-old mice. This study provides primary evidence for the connection between lipid metabolic disorder and hydrocephalus development. This may suggest that both hyperglyceridemia and hypercholesterolemia are harmful factors in hydrocephalus development because of adverse effects on TGF-β1/Smad signaling in the brain.

Finite element analysis of periventricular lucency in hydrocephalus: extravasation or transependymal CSF absorption?

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. 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. 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. 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.

Presentation of Novel Non-invasive Method for Intracranial Pressure Monitoring: ADC values Correlate with Intracranial Pressure Both in a Hydrocephalic Brain Phantom and Hydrocephalic Patients Pre- and Post- shunting

Presentation of Novel Non-invasive Method for Intracranial Pressure Monitoring: ADC values Correlate with Intracranial Pressure Both in a Hydrocephalic Brain Phantom and Hydrocephalic Patients Pre- and Post- shunting

A proposed role for efflux transporters in the pathogenesis of hydrocephalus.

Hydrocephalus is a common brain disorder that is treated only with surgery. The basis for surgical treatment rests on the circulation theory. However, clinical and experimental data to substantiate circulation theory have remained inconclusive. In brain tissue and in the ventricles, we see that osmotic gradients drive water diffusion in water-permeable tissue. As the osmolarity of ventricular CSF increases within the cerebral ventricles, water movement into the ventricles increases and causes hydrocephalus. Macromolecular clearance from the ventricles is a mechanism to establish the normal CSF osmolarity, and therefore ventricular volume. Efflux transporters, (p-glycoprotein), are located along the blood brain barrier and play an important role in the clearance of macromolecules (endobiotics and xenobiotics) from the brain to the blood. There is clinical and experimental data to show that macromolecules are cleared out of the brain in normal and hydrocephalic brains. This article summarizes the existing evidence to support the role of efflux transporters in the pathogenesis of hydrocephalus. The location of p-gp along the pathways of macromolecular clearance and the broad substrate specificity of this abundant transporter to a variety of different macromolecules are reviewed. Involvement of p-gp in the transport of amyloid beta in Alzheimer disease and its relation to normal pressure hydrocephalus is reviewed. Finally, individual variability of p-gp expression might explain the variability in the development of hydrocephalus following intraventricular hemorrhage.

104 Design and Evaluation of a Concentric Tube Robot for Minimally-Invasive Endoscopic Pediatric Neurosurgery

INTRODUCTION Current neuroendoscopic instruments lack the required size, accuracy, dexterity, and reachability to perform complex intraventricular procedures (i.e. endoscopic third ventriculostomy) [1-2]. Surgical robots offer a potential solution, however the unique and critically constrained workspace within the ventricle system poses major challenges. Concentric tube robots consist of telescoping, precurved, superelast ic n i t inol tubes that when rotated/translated relative to each other, allows precise control of robot shape and position [3]. We have developed a miniaturized, teleoperated concentric tube robot and implemented it on a validated silicone hydrocephalic brain phantom [4].

Fingerprint changes in CSF composition associated with different aetiologies in human neonatal hydrocephalus: glial proteins associated with cell damage and loss

BackgroundIn hydrocephalus an imbalance between production and absorption of cerebrospinal fluid (CSF) results in fluid accumulation, compression and stretching of the brain parenchyma. In addition, changes in CSF composition have a profound influence on the development and function of the brain and together, these can result in severe life-long neurological deficits. Brain damage or degenerative conditions can result in release of proteins expressed predominantly in neurons, astroglia, or oligodendroglia into the brain interstitial fluid, CSF and blood. Determination of such products in the CSF might be of value in diagnosing cause, aetiology and/or assessing the severity of the neurological damage in patients with hydrocephalus. We therefore analysed CSF from human neonates with hydrocephalus for these proteins to provide an insight into the pathophysiology associated with different aetiologies.MethodsCSF was collected during routine lumbar puncture or ventricular tap. Samples were categorized according to age of onset of hydrocephalus and presumed cause (fetal-onset, late-onset, post-haemorrhagic or spina bifida with hydrocephalus). Glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), vimentin and 2′ , 3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) were analysed through Western blotting of hydrocephalic CSF samples (n = 17) and compared with data from CSF of normal infants without neurological deficits (n = 8).ResultsGFAP was significantly raised only in CSF from post-haemorrhagic hydrocephalus while MBP was significantly raised in post-haemorrhagic and in spina bifida with hydrocephalus infants. Vimentin protein was only detected in some CSF samples from infants with late-onset hydrocephalus but not from other conditions. Surprisingly, CNPase was found in all neonatal CSF samples, including normal and hydrocephalic groups, although it was reduced in infants with late onset hydrocephalus compared with normal and other hydrocephalic groups.ConclusionsApart from CNPase, which is an enzyme, the markers investigated are intracellular intermediate filaments and would be present in CSF only if the cells are compromised and the proteins released. Raised GFAP observed in post-haemorrhagic hydrocephalus must reflect damage to astrocytes and ependyma. Raised MBP in post-haemorrhagic and spina bifida with hydrocephalus indicates damage to oligodendrocytes and myelin. Vimentin protein detected in some of the late-onset hydrocephalic samples indicates damage to glial and other progenitors and suggests this condition affects periventricular regions. The presence of CNPase in all CSF samples was unexpected and indicates a possible novel role for this enzyme in brain development/myelination. Less CNPase in some cases of late-onset hydrocephalus could therefore indicate changes in myelination in these infants. This study demonstrates differential glial damage and loss in the developing human neonatal hydrocephalic brain associated with different aetiologies.

Decorin prevents the development of juvenile communicating hydrocephalus

In post-haemorrhagic and other forms of communicating hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-β has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-β antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile communicating hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-β/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-β1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of hydrocephalus in juvenile rats by blocking transforming growth factor-β-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic communicating hydrocephalus.