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

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

Ependymal ciliary motion and their role in congenital hydrocephalus.

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.

Differentiating comorbidities and predicting prognosis in idiopathic normal pressure hydrocephalus using cerebrospinal fluid biomarkers: a review.

Idiopathic normal pressure hydrocephalus (iNPH) is a condition resulting from impaired cerebrospinal fluid (CSF) absorption and excretion characterized by a triad of symptoms comprising dementia, gait disturbance (impaired trunk balance), and urinary incontinence. CSF biomarkers not only assist in diagnosis but are also important for analyzing the pathology and understanding appropriate treatment indications. As the neuropathological findings characteristic of iNPH have yet to be defined, there remains no method to diagnose iNPH with 100% sensitivity and specificity. Neurotoxic proteins are assumed to be involved in the neurological symptoms of iNPH, particularly the appearance of cognitive impairment. The symptoms of iNPH can be reversed by improving CSF turnover through shunting. However, early diagnosis is essential as once neurodegeneration has progressed, pathological changes become irreversible and symptom improvement is minimal, even after shunting. Combining a variety of diagnostic methods may lead to a more definitive diagnosis and accurate prediction of the prognosis following shunt treatment. Identifying comorbidities in iNPH using CSF biomarkers does not contraindicate shunting-based intervention, but does limit the improvement in symptoms it yields, and provides vital information for predicting post-treatment prognosis.

Cerebrospinal fluid leak presented with the C1-C2 sign caused by spinal canal stenosis: a case report.

BACKGROUND: Intracranial hypotension is a disorder characterized by low cerebrospinal fluid (CSF) pressure typically caused by loss of CSF. Although some mechanisms account for the CSF leakage have been elucidated, spinal canal stenosis has never been reported as a pathological cause of intracranial hypotension. C1-C2 sign is a characteristic imaging feature, which indicates CSF collection between the spinous processes of C1 and C2, occasionally observed on magnetic resonance imaging (MRI) in patients with intracranial hypotension. CASE PRESENTATION: A 58-year-old man was presented to our institute with complaints of posterior cervical pain persisting for 3 months, along with numbness and muscle weakness of extremities. A fat suppression T2-weighted image of MRI illustrated fluid collection in the retrospinal region at C1-C2 level, and an 111In-DTPA cisternoscintigram clearly revealed the presence of CSF leakage into the same region. The MRI also showed stenosis in spinal canal at C3/4 level, and a computed tomography (CT) myelogram suggested a blockage at the same level. We gave a diagnosis as intracranial hypotension due to the CSF leakage, which might be caused by the spinal canal stenosis at C3/4 level. Despite 72 h of conservative therapy, a brain CT showed the development of bilateral subdural hematomas. We, therefore, performed burr-hole drainage of the subdural hematoma, blood-patch therapy at C1/2 level, and laminoplasty at C3-4 at the same time. Improvement of symptoms and imaging features which suggested the CSF leak and subdural hematoma were obtained post-operatively. CONCLUSION: The present case suggested the mechanism where the CSF leakage was revealed as fluid collection in the retrospinal region at C1-C2 level. Increased intradural pressure due to the spinal canal stenosis resulted in dural tear. CSF leaked into the epidural space and subsequently to the retrospinal region at C1-C2 level, due to the presence of spinal canal stenosis caudally as well as the vulnerability of the tissue structure in the retrospinal region at C1-C2 level. Thus, our theory supports the mechanisms of previously reported CSF dynamics associated to C1-C2 sign, and also, we suggest spinal canal stenosis as a novel etiology of intracranial hypotension.

Neuropsychological tests are useful for predicting comorbidities of idiopathic normal pressure hydrocephalus.

OBJECTIVES: Comorbidities of idiopathic normal pressure hydrocephalus (iNPH), such as Alzheimer's disease (AD) and Parkinson's spectrum (PS) disorder, can affect the long-term prognosis of cerebrospinal fluid (CSF) shunting. Therefore, it is important to be able to predict comorbidities in the early stage of the disease. This study aimed to predict the comorbidities of iNPH using neuropsychological tests and cognitive performance evaluation. MATERIALS & METHODS: Forty-nine patients with possible iNPH were divided into three groups: iNPH without AD or PS comorbidity (group-1), iNPH with AD comorbidity (group-2), and iNPH with PS comorbidity (group-3), according to CSF biomarkers such as phosphorylated tau and dopamine transporter imaging. Scores on the new EU-iNPH-scale, which is based on 4 neuropsychological tests (Rey Auditory Verbal Learning Test, Grooved Pegboard test, Stroop colour-naming test and interference test), were compared for each group. In addition, the scores before and 12 months after CSF shunting for each group were compared. RESULTS: EU-iNPH-scale using 4 neuropsychological tests could distinguish group-1 from group-2 or group-3 by area under the curve values of 0.787 and 0.851, respectively. Patients in group-1 showed a remarkable increase in memory and learning ability after surgery. Group-2 performed significantly poorer than group-1 patients on memory testing, but otherwise showed improvements in most of the neuropsychological tests. Group-3 performed significantly worse than group-1 patients-especially on Stroop tests-but showed post-surgery improvement on only the Stroop colour-naming test. CONCLUSIONS: The 4 neuropsychological tests of the EU-iNPH-scale can help predict iNPH comorbidities and evaluate the prognosis of CSF shunting.

Ventricular volumetry and free-water corrected diffusion tensor imaging of the anterior thalamic radiation in idiopathic normal pressure hydrocephalus.

BACKGROUND AND PURPOSE: The pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) has not been completely clarified. We investigated the brain structure in iNPH using automatic ventricular volumetry, single-tensor diffusion tensor imaging (DTI) and bi-tensor free-water (FW) imaging analyses while focusing on cognitive impairments before and after lumboperitoneal shunt surgery. MATERIALS AND METHODS: This retrospective study included 12 iNPH patients with structural magnetic resonance imaging (MRI) and diffusion MRI (dMRI) on a 3T-MRI scanner who underwent neuropsychological assessments before and after shunting and 8 healthy controls. Ventricular volumetry was conducted on structural MRI datasets using FreeSurfer. Ventricular volume was compared pre- and postoperatively. Correlation analyses were performed between ventricular volume or volume change and neuropsychological scores or score change. Tract-based spatial statistics were performed using dMRI datasets for group analyses between iNPH and controls and between pre- and post-surgery iNPH patients and for correlation analyses using neuropsychological scores. Tract-specific analyses were performed in the anterior thalamic radiation (ATR), followed by comparison and correlation analyses. RESULTS: The third ventricular volume was significantly decreased after shunting; its volume reduction negatively correlated with a neuropsychological improvement. Compared with controls, iNPH patients had lower fractional anisotropy and higher axial, radial, and mean diffusivities, and FW in the periventricular white matter including ATR, resulting in no difference in FW-corrected indices. Single-tensor DTI indices partially correlated with neuropsychological improvements, while FW-corrected indices had no correlations. CONCLUSION: Third ventricle enlargement is possibly linked to cognitive impairment and FW imaging possibly provides better white matter characterization in iNPH.

Quantitative Analysis of Change in Intracranial Volume After Posterior Cranial Vault Distraction and Frontal Orbital Advancement/Remodeling.

INTRODUCTION: Patients with craniosynostosis with shortened occipitofrontal diameter are mainly treated with posterior cranial vault distraction osteogenesis (PVDO) in our institution. If further intracranial volume (ICV) expansion is needed, additional treatment with frontal orbital advancement (FOA) is done. On the contrary, frontal orbital remodeling (FOR) is done for better aesthetic results. In this study, post-treatment ICV changes in patients with craniosynostosis treated with these methods have been investigated. METHODS: Patients who underwent FOA or FOR in addition to PVDO at Juntendo University Hospital between 2011 and 2017 were reviewed for patient characteristics and pre/postoperative ICV measurements using 3-dimensional computed tomography scans. RESULTS: Nine patients aged from 5 months to 6 years 8 months at the time of PVDO were included. For PVDO, the ICV change was 113 to 328 mL, and the enlargement ratio of ICV was 109% to 152%. Two patients were further operated with FOA while the remaining 7 with FOR. With FOA, ICV change was 73 to 138 mL, while enlargement ratio of ICV was 107% to 114%. With FOR, ICV change was 3 to 45 mL (mean 20 mL), while enlargement ratio of ICV was 100% to 103%. CONCLUSION: The PVDO is our first line of treatment for ICV expansion and posterior cranial fossa decompression in patients with severe craniosynostosis. The FOA is performed if extra ICV increase is necessary. This approach seems to enable larger ICV expansions compared with other conventional methods. The FOR should be reserved for patients in whom adequate ICV levels are achieved with PVDO yet additional frontal reshaping is necessary.

Spontaneous intracranial hypotension is diagnosed by a combination of lipocalin-type prostaglandin D synthase and brain-type transferrin in cerebrospinal fluid.

BACKGROUND: Spontaneous intracranial hypotension (SIH) is caused by cerebrospinal fluid (CSF) leakage. Definitive diagnosis can be difficult by clinical examinations and imaging studies. METHODS: SIH was diagnosed with the following criteria: (i) evidence of CSF leakage by cranial magnetic resonance imaging (MRI) findings of intracranial hypotension and/or low CSF opening pressure; (ii) no recent history of dural puncture. We quantified CSF proteins by ELISA or Western blotting. RESULTS: Comparing with non-SIH patients, SIH patients showed significant increase of brain-derived CSF glycoproteins such as lipocalin-type prostaglandin D synthase (L-PGDS), soluble protein fragments generated from amyloid precursor protein (sAPP) and "brain-type" transferrin (Tf). Serum-derived proteins such as albumin, immunoglobulin G, and serum Tf were also increased. A combination of L-PGDS and brain-type Tf differentiated SIH from non-SIH with sensitivity 94.7% and specificity 72.6%. CONCLUSION: L-PGDS and brain-type Tf can be biomarkers for diagnosing SIH. GENERAL SIGNIFICANCE: L-PGDS and brain-type Tf biosynthesized in the brain appears to be markers for abnormal metabolism of CSF.

The metopic-sagittal craniosynostosis-report of 35 operative cases.

PURPOSE: We have diagnosed 35 cases of the supposedly rare condition metopic-sagittal synostosis in the past 20 years. Here, we introduce their clinical symptoms, neuroradiological findings, and surgical treatment methods, as well as discuss the relevant literature. METHODS: Subjects included 35 patients (33 boys and 2 girls; mean age 4.2 years; range 1-8 years). Magnetic resonance imaging (MRI) confirmed that there were no abnormal findings in the brain. Thirty patients presented with symptoms including speech delay, hyperactivity, autistic tendency, motor impairment, self-mutilation, and panic/temper tantrum behaviors. No other congenital malformation was observed, and all cases were considered to be the non-syndromic type. The final diagnosis was made using three-dimensional computed tomography (3D-CT) scans. The surgery was done the fronto-orbital advancement in addition to remove the large parts of sphenoid bones including sphenoid ridges at the skull base and trimmed the calvarium as necessary to reduce pressure. RESULTS: Surgical intervention improved clinical symptoms in nearly all 35 patients; cosmetic problems in patients with scaphocephaly were also corrected. CONCLUSIONS: In the cases of child patients with metopic-sagittal synostosis who had clinical symptoms, surgical intervention improved such symptoms, suggesting its potential utility for metopic-sagittal synostosis with clinical symptoms. A surgical procedure focusing on the skull base was important for our successes. Based on the fact that metopic-sagittal synostosis was diagnosed in 35 patients at one institution over a relatively short period of time, this pathological condition may not be as rare as is currently believed.

Cost-effectiveness analysis of shunt surgery for idiopathic normal pressure hydrocephalus based on the SINPHONI and SINPHONI-2 trials.

BACKGROUND: We showed that ventriculoperitoneal (VP) shunt and lumboperitoneal (LP) shunt surgeries are beneficial for patients with idiopathic normal pressure hydrocephalus (iNPH) in the Study of Idiopathic Normal Pressure Hydrocephalus on Neurological Improvement (SINPHONI; a multicenter prospective cohort study) and in SINPHONI-2 (a multicenter randomized trial). Although therapeutic efficacy is important, cost-effectiveness analysis is equally valuable. METHODS: Using both a set of assumptions and using the data from SINPHONI and SINPHONI-2, we estimated the total cost of treatment for iNPH, which consists of medical expenses (e.g., operation fees) and costs to the long-term care insurance system (LCIS) in Japan. Regarding the natural course of iNPH patients, 10% or 20% of patients on each modified Rankin Scale (mRS) show aggravation (aggravation rate: 10% or 20%) every 3 months if the patients do not undergo shunt surgery, as described in a previous report. We performed cost-effectiveness analyses for the various scenarios, calculating the quality-adjusted life year (QALY) and the incremental cost-effective ratio (ICER). Then, based on the definition provided by a previous report, we assessed the cost-effectiveness of shunt surgery for iNPH. RESULTS: In the first year after shunt surgery, the ICER of VP shunt varies from 29,934 to 40,742 USD (aggravation rate 10% and 20%, respectively) and the ICER of LP shunt varies from 58,346 to 80,392 USD (aggravation rate 10% and 20%, respectively), which indicates that the shunt surgery for iNPH is a cost-effective treatment. In the 2nd postoperative year, the cost to the LCIS will continue to decrease because of the lasting improvement of the symptoms due to the surgery. The total cost for iNPH patients will show a positive return on investment in as soon as 18 months (VP) and 21 months (LP), indicating that shunt surgery for iNPH is a cost-effective treatment. CONCLUSIONS: Because the total cost for iNPH patients will show a positive return on investment within 2 years, shunt surgery for iNPH is a cost-effective treatment and therefore recommended. The SINPHONI-2 study was registered with the University Hospital Medical Information Network Clinical Trials registry: UMIN000002730) SINPHONI was registered with ClinicalTrials.gov, no. NCT00221091.

Prospective estimation of mean axon diameter and extra-axonal space of the posterior limb of the internal capsule in patients with idiopathic normal pressure hydrocephalus before and after a lumboperitoneal shunt by using q-space diffusion MRI.

OBJECTIVES: To prospectively estimate the mean axon diameter (MAD) and extracellular space of the posterior limb of the internal capsule (PLIC) in patients with idiopathic normal pressure hydrocephalus (iNPH) before and after a lumboperitoneal (LP) shunting operation using q-space diffusion MRI analysis. METHODS: We studied 12 consecutive patients with iNPH and 12 controls at our institution. After conventional magnetic resonance imaging (MRI), q-space image (QSI) data were acquired with a 3-T MRI scanner. The MAD and extra-axonal space of the PLIC before and after LP shunting were calculated using two-component q-space imaging analyses; the before and after values were compared. RESULTS: After LP shunt surgery, the extracellular space of the PLIC was significantly higher than that of the same patients before the operation (one-way analysis of variance (ANOVA) with Scheffé's post-hoc test, P = 0.024). No significant differences were observed in the PLIC axon diameters among normal controls or in patients before and after surgery. CONCLUSION: Increases in the root mean square displacement in the extra-axonal space of the PLIC in patients with iNPH after an LP shunt procedure are associated with the microstructural changes of white matter and subsequent abatement of patient symptoms. KEY POINTS: • Q-space diffusion MRI provides information on microstructural changes in the corticospinal tract • Lumboperitoneal (LP) shunting operation is useful for idiopathic normal pressure hydrocephalus • Q-space measurement may be a biomarker for the effect of the LP shunt procedure.

In vitro performance of the fixed and adjustable gravity-assisted unit with and without motion-evidence of motion-induced flow.

BACKGROUND: Anti-siphon devices and gravitational-assisted valves have been introduced to counteract the effects of overdrainage after implantation of a shunt system. The study examined the flow performance of two gravitational-assisted valves (shunt assistant - SA and programmable shunt assistant - proSA, Miethke & Co. KG, Potsdam, Germany) in an in vitro shunt laboratory with and without motion. METHODS: An in vitro laboratory setup was used to model the cerebrospinal fluid (CSF) drainage conditions similar to a ventriculo-peritoneal shunt and to test the SA (resistance of +20 cmH2O in 90°) and proSA (adjustable resistance of 0 to +40 cmH2O in 90°). The differential pressure (DP) through the simulated shunt and tested valve was adjusted between 0 and 60 cmH2O by combinations of different inflow pressures (40, 30, 20, 10, and 0 cmH2O) and the hydrostatic negative outflow pressure (0, -20, and -40 cmH2O) in several differing device positions (0°, 30°, 60°, and 90°). In addition, the two devices were tested under vertical motion with movement frequencies of 2, 3, and 4 Hz. RESULTS: Both gravity-assisted units effectively counteract the hydrostatic effect in relation to the chosen differential pressure. The setting the proSA resulted in flow reductions in the 90° position according to the chosen resistance of the device. Angulation-related flow changes were similar in the two devices in 30-90° position, however, in the 0-30° position, a higher flow is seen in the proSA. Repeated vertical movement significantly increased flow through both devices. While with the proSA a 2-Hz motion was not able to induce additional flow (0.006 ± 0.05 ml/min), 3- and 4-Hz motion significantly induced higher flow values (3 Hz: +0.56 ± 0.12 ml/min, 4 Hz: +0.54 ± 0.04 ml/min). The flow through the SA was not induced by vertical movements at a low DP of 10 cmH2O at all frequencies, but at DPs of 30 cmH2O and higher, all frequencies significantly induced higher flow values (2 Hz: +0.36 ± 0.14 ml/min, 3 Hz: +0.32 ± 0.08 ml/min, 4 Hz: +0.28 ± 0.09 ml/min). CONCLUSIONS: In a static setup, both tested valves effectively counteracted the hydrostatic effect according to their adjusted or predefined resistance in vertical position. Motion-induced increased flow was demonstrated for both devices with different patterns of flow depending on applied DP and setting of the respective valve. The documented increased drainage should be considered when selecting appropriate valves and settings in very active patients.

Quantitative Analysis of Change in Intracranial Volume After Posterior Cranial Vault Distraction.

Posterior cranial vault distraction is considered to be more effective for increasing intracranial volume than fronto-orbital advancement or anterior cranial vault expansion, but the changes in intracranial volumes after posterior cranial vault distraction remain unclear. The changes in intracranial volume were investigated in patients of premature craniosynostosis treated by this technique. Seven patients, 3 boys and 4 girls aged from 5 months to 3 years 3 months (mean 23 months) at operation, with craniosynostosis underwent posterior cranial vault distraction at Juntendo University Hospital from 2011 to 2014. Patient characteristics, length of distraction, and pre- and postoperative computed tomography findings were reviewed. Total intracranial volume, including the supratentorial space and posterior cranial fossa, was measured using the workstation functions on three-dimensional computed tomography scans. Posterior distraction was performed without severe complications except in 2 patients requiring additional surgeries. The distraction length was 22.3 to 39 mm (mean 31 mm), the intracranial volume change was 144 to 281 mL (mean 192 mL), and the enlargement ratio of intracranial volume was 113% to 134% (mean 121%). The present quantitative analysis of intracranial volume change after posterior distraction showed greater increases in intracranial volume compared with previous reports. Furthermore, intracranial volumes in our patients became nearly normal and were maintained for the follow-up period (maximum 13 months). Posterior cranial vault distraction is very effective to increase cranial volume, so may be the first choice of treatment in patients of craniosynostosis.

Cerebrospinal fluid drainage through the diploic and spinal epidural veins.

The aim of this study was to quantitatively evaluate the function of the cranial diploic and spinal epidural veins as cerebrospinal fluid (CSF) drainage pathways by measuring lipocalin-type prostaglandin D synthase (PGDS) and cystatin C (CysC) dissolved in the blood of these veins. This was a prospective study involving 51 consecutive patients, 31 males and 20 females, who underwent 41 cranial and 10 spinal surgeries. Intraoperatively, peripheral venous blood and diploic venous blood, or peripheral venous blood and spinal epidural venous blood samples were simultaneously collected and immediately centrifuged. For all samples, dissolved albumin (for reference), PGDS and CysC were measured using an enzyme-linked immunosorbent assay. The diploic vein/peripheral vein ratios in five cranial locations and epidural vein/peripheral vein ratios were calculated and statistically evaluated for the three biomarkers. For PGDS, the diploic vein/peripheral vein ratio was significantly increased in the frontal (P = 0.011), temporal (P = 0.028), parietal (P = 0.046) and skull base (P = 0.039), while it did not reach statistical significance for CysC. For patients older than 45 years, the diploic vein/peripheral vein ratio for PGDS was significantly decreased in the frontal region (P = 0.028), and the epidural vein/peripheral vein ratio for CysC was significantly decreased (P = 0.014). These results show that the diploic veins constitute CSF drainage pathways with heterogeneous functional intensity at different cranial locations. Compared with the diploic veins, spinal epidural veins seem to drain less CSF. The cranial diploic and spinal epidural veins may jointly function as an alternative, age-related trans-dural CSF drainage system.

[Case Report of Cerebellar Vermis Arteriovenous Malformation Presenting with Hydrocephalus due to Aqueductal Stenosis].

A 56-year-old man complained of gait disturbance and confused thinking. Magnetic resonance imaging(MRI)revealed an arteriovenous malformation(AVM)of the cerebellar vermis(Spetzler-Martin grade IV)causing hydrocephalus. One dilated precentral cerebellar vein was compressing the aqueduct. After feeder embolization over 3 sessions using N-butyl cyanoacrylate(NBCA), the nidus was reduced to one-third in size. However, symptoms remained unimproved, and endoscopic third ventriculostomy(ETV)was performed. The third ventricle showed thinning of the floor, with a fenestration in part of the floor. Radiological findings and clinical symptoms improved, and the patient returned home after rehabilitation. The condition of the patient remained stable as of six months later. On angiography, the draining vein showed a pressure of 20 mmHg with no change in the residual AVM. Embolization alone achieved a reduction in nidus volume, but could not reduce venous pressure, and combination therapy including ETV proved necessary. Cases with hydrocephalus due to aqueductal stenosis by AVM are extremely rare. This pathology is discussed with reference to the literature.

The somatic GNAQ mutation c.548G>A (p.R183Q) is consistently found in Sturge-Weber syndrome.

Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by capillary malformation (port-wine stains), and choroidal and leptomeningeal vascular malformations. Previously, the recurrent somatic mutation c.548G>A (p.R183Q) in the G-α q gene (GNAQ) was identified as causative in SWS and non-syndromic port-wine stain patients using whole-genome sequencing. In this study, we investigated somatic mutations in GNAQ by next-generation sequencing. We first performed targeted amplicon sequencing of 15 blood-brain-paired samples in sporadic SWS and identified the recurrent somatic c.548G>A mutation in 80% of patients (12 of 15). The percentage of mutant alleles in brain tissues of these 12 patients ranged from 3.6 to 8.9%. We found no other somatic mutations in any of the seven GNAQ exons in the remaining three patients without c.548G>A. These findings suggest that the recurrent somatic GNAQ mutation c.548G>A is the major determinant genetic factor for SWS and imply that other mutated candidate gene(s) may exist in SWS.

Classification of Chronic Hydrocephalus in Adults: A Systematic Review and Analysis.

BACKGROUND: Chronic hydrocephalus in adults (CHiA) includes all nonacute forms of hydrocephalus occurring in adulthood. It covers a spectrum of disorders. Some of these have relatively agreed on definitions, while others are less well characterized. The existing medical classification systems lack adequate structure and are neither clinically oriented nor easy to use, which severely hampers research and clinical care efforts. METHODS: A systematic literature review and data analysis were performed, focusing on the terms "adult hydrocephalus" and "classification," using the PubMed, Scopus, and Cochrane Library databases. Data on terminology, definitions, patient demographics, symptom duration, and clinical presentations were extracted, analyzed, and compiled. A Delphi process was followed to define CHiA disorders. RESULTS: A total of 33 studies collectively used 48 terms to define various CHiA disorders. Different terms were used to describe similar conditions. CHiA disorders were found to be clustered into 7 distinctive clinical entities based on the clinical characteristics. CONCLUSIONS: An evidence-based new clinical classification for CHiA is suggested. Our review identified gaps in knowledge and areas for further research.

Microstructural changes of the corticospinal tract in idiopathic normal pressure hydrocephalus: a comparison of diffusion tensor and diffusional kurtosis imaging.

INTRODUCTION: The goals of this study were to examine the usefulness of diffusional kurtosis imaging (DKI) for assessing microstructural changes in the compressed corticospinal tract (CST) among patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Eleven patients with iNPH (mean age: 73.6 years, range: 65-84), who underwent 3-T magnetic resonance imaging, including DKI before surgery, were recruited. Six age-matched, healthy subjects (mean age: 69.8 years, range: 60-75) served as the control group. DKI and diffusion tensor imaging parameters were calculated and compared between the iNPH and the control groups using tract-specific analysis of the CST at the level of the lateral ventricle. RESULTS: Mean diffusional kurtosis (DK) and axial diffusion kurtosis were significantly lower in iNPH patients. However, apparent diffusion coefficient, fractional anisotropy, and axial eigenvalue (λ1) were significantly higher in the iNPH group than in the control group. CONCLUSIONS: The mechanical pressure caused by ventricular enlargement in iNPH patients might induce formation of well-aligned fiber tracts and increased fiber density in the CST, resulting in decreased DK. DKI is able to depict both the altered microstructure and water molecule movement within neural axons and intra- or extracellular space. In addition, the investigated DKI parameters provide different information about white matter relative to conventional diffusional metrics for iNPH.

Genetic studies of myelomeningocele.

INTRODUCTION: Myelomeningocele is one of the major congenital malformations involving the central nervous system. It is caused by a disruption of the neural tube closure, which is completed at 3-4 weeks of gestation. DISCUSSION: Multidisciplinary approach is necessary to treat and support this malformation which is a huge burden to the patient, family, and the society. This is a characteristic anomaly that it is known that taking folic acid during the periconceptional period, it is possible to reduce the risk of having a neural tube defect (NTD). Although folate fortification had dramatically reduced the incidence, it was not possible to diminish the risk. To date, many studies have been conducted focusing on candidate genes related to folate and glucose metabolism. We will describe a brief review of genetic etiology of candidate genes of metabolic pathways of folate and glucose, animal models of NTDs, and finally recent studies of microRNA.