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OBJECTIVE The objective of this study was to analyze the effect of concomitant Parkinson’s disease (PD) and PD dementia (PD/PDD) on the course of idiopathic normal pressure hydrocephalus (iNPH), especially as related to the outcome of lumboperitoneal shunt (LPS) surgery. METHODS The authors retrospectively analyzed patients with iNPH without accompanying disorders (iNPH alone [iNPHa]) and iNPH concomitant with PD/PDD (iNPHc+PD/PDD) who had presented to their department between 2010 and 2019. The diagnosis of iNPHc+PD/PDD was established using the diagnostic criteria of the Movement Disorder Society. The effect of LPS surgery on clinical symptoms and striatum volumes was evaluated. RESULTS Thirty-three patients with iNPHa and 23 patients with iNPHc+PD/PDD were identified. Comorbid PD/PDD significantly worsened clinical outcome as measured by the iNPH grading scale, modified Rankin Scale (mRS), and Hoehn and Yahr (HY) scale. LPS surgery improved the iNPH score including gait disturbance (p < 0.01), cognitive impairment (p = 0.02), and urinary disturbance (p < 0.01) in iNPHa and improved gait disturbance (p = 0.01) and urinary disturbance (p = 0.03) in iNPHc+PD/PDD for 1 year. Comorbid synucleinopathies maintained worse mRS scores and HY stages for 3 years, and LPS surgery extended overall survival (p = 0.003), as well as the period of sustained mRS scores (p = 0.04) and HY stages (p = 0.004) in iNPHc+PD/PDD. Both caudate and putamen volumes were reduced in iNPHa (p < 0.01) compared to those in controls and in patients with iNPHc+PD/PDD compared to those in patients with PD/PDD (p < 0.01), and LPS surgery restored caudate volumes in both groups. CONCLUSIONS These results revealed that comorbid PD/PDD deteriorates the clinical course of iNPH and that LPS surgery is recommended regardless of this comorbidity.

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.

Background: The amyloid-β oligomers, consisting of 10–20 monomers (AβO10–20), have strong neurotoxicity and are associated with cognitive impairment in Alzheimer’s disease (AD). However, their role in patients with idiopathic normal pressure hydrocephalus (iNPH) is poorly understood. Objective: We hypothesized that cerebrospinal fluid (CSF) AβO10–20 accumulates in patients with iNPH, and its clearance after CSF shunting contributes to neurological improvement. We measured CSF AβO10–20 levels before and after CSF shunting in iNPH patients evaluating their diagnostic and prognostic role. Methods: We evaluated two iNPH cohorts: “evaluation” (cohort-1) with 32 patients and “validation” (cohort-2) with 13 patients. Comparison cohorts included: 27 neurologically healthy controls (HCs), and 16 AD, 15 Parkinson’s disease (PD), and 14 progressive supranuclear palsy (PSP) patients. We assessed for all cohorts CSF AβO10–20 levels and their comprehensive clinical data. iNPH cohort-1 pre-shunting data were compared with those of comparison cohorts, using cohort-2 for validation. Next, we compared cohort-1’s clinical and CSF data: 1) before and after CSF shunting, and 2) increased versus decreased AβO10–20 levels at baseline, 1 and 3 years after shunting. Results: Cohort-1 had higher CSF AβO10–20 levels than the HCs, PD, and PSP cohorts. This result was validated with data from cohort-2. CSF AβO10–20 levels differentiated cohort-1 from the PD and PSP groups, with an area under receiver operating characteristic curve of 0.94. AβO10–20 levels in cohort-1 decreased after CSF shunting. Patients with AβO10–20 decrease showed better cognitive outcome than those without. Conclusion: AβO10–20 accumulates in patients with iNPH and is eliminated by CSF shunting. AβO10–20 can be an applicable diagnostic and prognostic biomarker.

Idiopathic normal pressure hydrocephalus (iNPH) is a surgically treatable syndrome commonly observed in older adults. However, it is unclear whether clinical improvements after surgery can effectively reduce the long-term care burden (LTCB). In this study, we determined whether shunt surgery was effective in decreasing LTCB. We also investigated the degree of variability in patients and hospitals, using data from the iNPH multicenter study. This study involved 69 participants who underwent lumboperitoneal shunt surgery with follow-up for 12 months. A generalized linear mixed model was applied to analyze the fixed and random effects simultaneously. Regarding LTCB, the disability grades improved significantly. Although the dementia grades also improved, it was not statistically significant. The differences in the LTCB grades in most patients were within the range of the 95% confidence intervals, while in the case of hospitals, some were often out of the range. Further studies are needed to improve dementia in patients with iNPH. The incorporation of random variables, such as hospitals, is important for the analysis of data from multicenter studies.

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.

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.

Spontaneous intracranial hypotension (SIH) is caused by cerebrospinal fluid (CSF) leakage. Patients with SIH experience postural headaches, nausea, etc., due to CSF hypovolemia. Imaging studies and clinical examinations, such as radioisotope (RI) scintigraphy, are useful for diagnosing SIH. However, 20-30% of patients do not show typical morphology and clinical test results. We previously reported that CSF contains transferrin (Tf) isoforms: “brain-type” Tf derived from the choroid plexus and “serum-type” Tf derived from blood. We showed that both isoforms increased in the CSF of patients with SIH by Western blotting. In the present study, we demonstrate that conventional ELISA for quantifying total Tf is useful for diagnosing SIH more accurately than Western blotting. In addition, SIH with chronic subdural hematoma (CSDH) was also accurately diagnosed. Total Tf in the CSF can serve as a useful biomarker for diagnosing SIH with or without CSDH.

The effect of temporal sampling rate (TSR) on perfusion parameters has not been fully investigated in Moyamoya disease (MMD); therefore, this study evaluated the influence of different TSRs on perfusion parameters quantitatively and qualitatively by applying simultaneous multi-slice (SMS) dynamic susceptibility contrast-enhanced MR imaging (DSC-MRI).DSC-MRI datasets were acquired from 28 patients with MMD with a TSR of 0.5 s. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and time to maximum tissue residue function (Tmax) were calculated for eight TSRs ranging from 0.5 to 4.0 s in 0.5-s increments that were subsampled from a TSR of 0.5 s datasets. Perfusion measurements and volume for chronic ischemic (Tmax ≥ 2 s) and non-ischemic (Tmax2 s) areas for each TSR were compared to measurements with a TSR of 0.5 s, as was visual perfusion map analysis.CBF, CBV, and Tmax values tended to be underestimated, whereas MTT and TTP values were less influenced, with a longer TSR. Although Tmax values were overestimated in the TSR of 1.0 s in non-ischemic areas, differences in perfusion measurements between the TSRs of 0.5 and 1.0 s were generally minimal. The volumes of the chronic ischemic areas with a TSR ≥ 3.0 s were significantly underestimated. In CBF and CBV maps, no significant deterioration was noted in image quality up to 3.0 and 2.5 s, respectively. The image quality of MTT, TTP, and Tmax maps for the TSR of 1.0 s was similar to that for the TSR of 0.5 s but was significantly deteriorated for the TSRs of ≥ 1.5 s.In the assessment of MMD by SMS DSC-MRI, application of TSRs of ≥ 1.5 s may lead to deterioration of the perfusion measurements; however, that was less influenced in TSRs of ≤ 1.0 s.

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.

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.

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.

BackgroundCongenital hydrocephalus occurs with some inheritable characteristics, but the mechanisms of its development remain poorly understood. Animal models provide the opportunity to identify potential genetic causes in this condition. The Hydrocephalus-Texas (H-Tx) rat strain is one of the most studied animal models for investigating the causative genetic alterations and analyzing downstream pathogenetic mechanisms of congenital hydrocephalus.MethodsComparative genomic hybridization (CGH) array on non-hydrocephalic and hydrocephalic H-Tx rats was used to identify causative genes of hydrocephalus. Targeted gene knockout mice were generated by CRISPR/Cas9 to study the role of this gene in hydrocephalus. ResultsCGH array revealed a copy number loss in chromosome 16p16 region in hydrocephalic H-Tx rats, encompassing the Ptpn20 gene, without change in most non-hydrocephalic H-Tx rats. Ptpn20-knockout (Ptpn20-/-) mice were generated and found to develop ventriculomegaly. Furthermore, high expression of phosphorylated Na-K-Cl cotransporter 1 (pNKCC1) was identified in the choroid plexus (CP) epithelium of mice lacking Ptpn20. ConclusionsThe high level of pNKCC1 in CP epithelium may cause the overproduction of cerebrospinal fluid and contribute to the formation of hydrocephalus in Ptpn20-/- mice. Ptpn20 may be a potential therapeutic target in the treatment of hydrocephalus.

BackgroundThe aim of this study was to evaluate the water diffusivity changes along the perivascular space after lumboperitoneal shunt (LPS) surgery in idiopathic normal pressure hydrocephalus.MethodsNine patients diagnosed with idiopathic normal pressure hydrocephalus (iNPH; three men and six women, mean age ± SD = 75.22 ± 5.12 years) according to the guidelines for iNPH in Japan were included in the study. Post-LPS surgery, six patients with iNPH who exhibited improvement in symptoms were defined as responder subjects, while three patients with iNPH who did not were defined as non-responder subjects. We calculated the mean analysis along the perivascular space (ALPS) index of the left and right hemispheres and compared the differences between pre- and post-LPS surgery mean ALPS indices in iNPH patients. In the responder or non-responder subjects, the mean ALPS indices in the pre- and post-operative iNPH groups were compared using Wilcoxon signed-rank tests. Next, correlation analyses between pre- and post-operation changes in the mean ALPS index and clinical characteristics were conducted.ResultsThe mean ALPS index of the post-operative iNPH group was significantly higher than that of the pre-operative iNPH group (p = 0.021). In responder subjects, the mean ALPS index of the post-operative iNPH group was significantly higher than that of the pre-operative iNPH group (p = 0.046). On the other hand, in the non-responder subjects, the mean ALPS index of the post-operative iNPH group was not significantly different compared to the pre-operative iNPH group (p = 0.285). The mean ALPS index change was not significantly correlated with changes in the Mini-Mental State Examination (MMSE) score (r = −0.218, p = 0.574), Frontal Assessment Battery (FAB) score (r = 0.185, p = 0.634), Trail Making Test A (TMTA) score (r = 0.250, p = 0.516), and Evans' index (r = 0.109, p = 0.780). In responder subjects, the mean ALPS index change was significantly correlated with Evans' index in pre-operative patients with iNPH (r = 0.841, p = 0.036).ConclusionThis study demonstrates the improved water diffusivity along perivascular space in patients with iNPH after LPS surgery. This could be indicative of glymphatic function recovery following LPS surgery.

Background In many brain volumetry reports, data from both controls and patients have been used to create the diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL) templates for spatial normalization, whereas some studies used data from only the control group. Purpose To investigate the association between lesion detection and the processes used in creating DARTEL template in group comparisons with voxel-based morphometry. Material and Methods Three-dimensional T1-weighted MRI data of 31 healthy controls, 31 patients with Alzheimer’s disease, and 31 patients with idiopathic normal pressure hydrocephalus were obtained using a 3-T magnetic resonance scanner. Segmented gray matter images were then deformed into three types of DARTEL templates using the Statistical Parametric Mapping 12 software. Results Processes 1 (DARTEL template with all individuals) and 2 (DARTEL template with healthy controls) showed significant lesions, as observed in previous reports, whereas process 3 (DARTEL template with individuals divided into two groups) showed significantly larger lesions than those noted with processes 1 and 2. Conclusion The present study demonstrated that lesion detection depends on the processes used in the creation of the DARTEL template.

Background Patients with idiopathic normal-pressure hydrocephalus (iNPH) are typically older adults with multiple comorbidities that are associated with a reduction in the efficacy of iNPH treatment via cerebrospinal fluid (CSF) shunt placement. Objective The present study aimed to investigate the effectiveness of CSF shunt for iNPH using data from a nationwide epidemiological survey in Japan. Methods We examined 1,423 patients (581 women) aged ≥60 years (median age [25%-75%]: 77 [73-80] years) who were diagnosed with iNPH following a hospital visit in 2012. Patients who experienced an improvement of at least one modified Rankin Scale (mRS) grade after the CSF shunt were classified as "improvement" while the remaining patients were classified as "non-improvement." The efficacy of the shunt intervention (n = 842) was analyzed using a binomial logistic regression analysis. Results An analysis of risk factors associated with shunt placement in patients with mRS grade 2 revealed an association between comorbid chronic ischemic lesions (odds ratio [OR], 2.28; 95% confidence interval [CI], 1.11-4.67; p = 0.025) and cervical spondylosis (OR, 3.62; 95% CI, 1.15-11.34; p = 0.027). Patients with mRS grade 3 at study entry had an association with comorbid Alzheimer's disease (OR, 3.02; 95% CI, 1.44-6.31; p = 0.003). Conclusions The results presented here showed that any age-related risk is minimal and should not be cause for rejection of surgical treatment options. Clinical decisions regarding CSF shunt should be individualized to each patient, with adequate consideration of the relative risks and benefits, including maximizing a healthy life expectancy.

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.

Introduction Our previous community-based study demonstrated that some individuals with AVIM [asymptomatic ventriculomegaly with features of idiopathic normal pressure hydrocephalus (iNPH) on magnetic resonance imaging (MRI)] progressed to iNPH in several years. In this hospital-based study, we investigated the progression rate from AVIM to iNPH and its possible predictors. Methods We conducted a prospective study of participants with AVIM from several medical institutions/hospitals in Japan. AVIM is defined as “asymptomatic ventriculomegaly with features of iNPH on MRI”; in the present study, asymptomatic was defined as “0 (no symptoms) or 1 (presence of only subjective, but not objective, symptoms) on the iNPH Grading Scale (iNPH-GS).” We also measured possible predicting factors for AVIM-to-iNPH progression, including age, sex, body weight, blood pressure, diabetes mellitus, dyslipidemia, history of mental disease/head injury/sinusitis/smoking/alcohol-intake, Evans index, and the presence of DESH (disproportionately enlarged subarachnoid-space hydrocephalus) findings on brain MRI, and analyzed these potential predictive values. Results In 2012, 93 participants with AVIM were registered and enrolled in the study. Of these, 52 participants were able to be tracked for three years (until 2015). Of the 52 participants, 27 (52%) developed iNPH during the follow-up period (11 definite, 6 probable, and 10 possible iNPH), whereas 25 participants remained asymptomatic in 2015. Among the possible predictive factors examined, the baseline scores of iNPH-GS predicted the AVIM-to-iNPH progression. Conclusions The multicenter prospective study demonstrated that the progression rate from AVIM to iNPH was ~17% per year, and the baseline scores of iNPH-GS predicted the AVIM-to-iNPH progression.

Background The amyloid-beta (Aβ) oligomer has strong neurotoxicity and is associated with cognitive impairment in Alzheimer’s disease (AD). However, its role in patients with idiopathic normal pressure hydrocephalus (iNPH) is poorly understood. We hypothesised that cerebrospinal fluid (CSF) stagnation leads to Aβ oligomer accumulation in patients with iNPH. We measured CSF Aβ oligomer levels before and after CSF shunting in patients with iNPH. Methods We evaluated two iNPH cohorts: an analysis cohort (cohort-1) with 52 patients and a validation cohort (cohort-2) with 13 patients. For comparison cohorts, we recruited 27 neurologically normal controls (NCs), 16 patients with AD, 15 patients with Parkinson’s disease (PD), and 14 patients with progressive supranuclear palsy (PSP). We measured CSF Aβ oligomer levels and assessed participants’ neurological statuses. We then compared the iNPH cohorts’ pre-shunting measurements with the comparison groups’ measurements and compared cohort-1’s measurements recorded before and after CSF shunting. Results iNPH cohort-1 had higher CSF Aβ oligomer levels than the NC, PD, and PSP cohorts. This result was validated with data from iNPH cohort-2. CSF Aβ oligomer levels differentiated iNPH cohort-1 from the PD and PSP groups, with an area under receiver operating characteristic curve of 0.94. Aβ oligomer levels in iNPH cohort-1 decreased after CSF shunting. However, there was no correlation between Aβ oligomer levels and cognitive functions in iNPH cohort-1. Conclusion The Aβ oligomer accumulates in patients with iNPH patients but can be eliminated with CSF shunting, suggesting that CSF stagnation causes Aβ oligomer accumulation in iNPH.

Background Alzheimer's disease (AD) pathology in idiopathic normal pressure hydrocephalus (iNPH) contributes to poor shunt responses. Amyloid-β 1- 42 (Aβ42) toxic conformer was recently identified with features of rapid oligomerization, strong neurotoxicity and synaptotoxicity. Objective This observational study points to Aβ42 toxic conformer as a biomarker for AD pathology and for poor postoperative prognosis in patients with iNPH. Methods The first cohort consisted of patients with AD (n = 17) and iNPH (n = 17), and cognitively normal individuals (CN, n = 12). The second cohort, consisted of 51 patients with iNPH, was divided into two groups according to phosphorylated Tau (pTau) level (low- and high-pTau groups); the low-pTau group was further subdivided according to one-year postoperative change in Aβ42 toxic conformer ratio (%) [Aβ42 toxic conformer/Aβ42×100] (decreased- and increased-conformer subgroups). Enzyme-linked immunosorbent assay was used to measure pTau, Aβ42, and Aβ42 toxic conformer in cerebrospinal fluid. Outcomes were evaluated using neuropsychological tests one- and two-years postoperatively. Results In the first cohort, Aβ42 toxic conformer ratio in the iNPH group (10.8%) was significantly higher than that in the CN group (6.3%) and significantly lower than that in the AD group (17.2%). In the second cohort, the high-pTau group showed cognitive decline two-years postoperatively compared to baseline. However, the low-pTau group showed favorable outcomes one-year postoperatively; furthermore, the increased-conformer subgroup showed cognitive decline two-years postoperatively while the decreased-conformer subgroup maintained the improvement. Conclusions Change in Aβ42 toxic conformer ratio predicts long-term cognitive outcome in iNPH, even in the low-pTau group.

Idiopathic normal pressure hydrocephalus (iNPH) is a dementia-inducing disorder. Primary cause of iNPH is speculated to be a reduction of cerebrospinal fluid (CSF) absorption, which secondarily induces hydrocephalus, compression of brain, and reduction of CSF production. Patients are treated by surgically inserting a shunt to deliver excess CSF to the abdominal cavity. The prognosis for cognitive improvement after shunt surgery has been difficult to predict. We therefore investigated various CSF proteins, hoping to find a biomarker predictive of cognitive performance one to two years after shunt surgery. CSF proteins of 34 iNPH and 15 non-iNPH patients were analysed by Western blotting, revealing two glycan isoforms of transferrin (Tf); 'brain-type' Tf with N-acetylglucosaminylated glycans and 'serum-type' Tf with α2, 6-sialylated glycans. Brain-type Tf levels decreased in iNPH but rapidly returned to normal levels within 1-3 months after shunt surgery. This change was positively correlated with recovery from dementia, per Mini-Mental State Examination and Frontal Assessment Battery scores at 11.8 ± 7.7 months post-operation, suggesting that brain-type Tf is a prognostic marker for recovery from dementia after shunt surgery for iNPH. Histochemical staining with anti-Tf antibody and an N-acetylglucosamine-binding lectin suggests that brain-type Tf is secreted from choroid plexus, CSF-producing tissue.

Background Treating idiopathic normal pressure hydrocephalus (iNPH) with lumboperitoneal shunts (LPSs) may cause cerebrospinal fluid (CSF) overdrainage. Objective To investigate whether LPSs, including gravitational "add-on" and programmable pressure valves (PPVs/+GVs), reduce complications and improve outcomes. Methods We compared PPVs/+small lumen abdominal catheters (SLs) to PPVs/+GVs using different opening pressures for supine and standing positions. We analyzed 115 patients with iNPH in 2 consequent cohorts: 48 patients receiving LPSs with PPVs/+SLs and 67 patients receiving LPSs with PPVs/+GVs. The modified Rankin Scale (mRS), Japan iNPH grading scale, Mini Mental State Examination, Frontal Assessment Battery, and CSF biomarkers were evaluated. Results Comparisons of postoperative clinical factors in 64 patients in the PPV/+SL and PPV/+GV groups using 1:1 propensity score matching revealed differences in the mean (±standard deviation) postoperative mRS (2.65 ± 1.07 vs 2.16 ± 1.02, P = .049) and gait disturbance scores (1.97 ± 1.03 vs 1.39 ± 0.92, P = .011). Thus, outcomes improved in the LPS group with the GV. Serious and nonserious adverse event rates for the PPV/+SL and PPV/+GV groups were 22.9% and 19.4% (P = .647) and 38% and 17.9% (P = .018), respectively, indicating higher rates of subdural collections for the PPV/+SL group. Conclusion This is the first study to examine LPS treatment for iNPH using a GV in tandem with a PPV. Our results suggest that the CSF shunt flow volume is restricted in the standing position and maintained in the supine position, thus improving iNPH symptoms. This may reduce intracranial CSF hypotension-related complications.

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. 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. Surgical intervention improved clinical symptoms in nearly all 35 patients; cosmetic problems in patients with scaphocephaly were also corrected. 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.

The symptoms of idiopathic normal pressure hydrocephalus (iNPH) can be improved by shunt surgery, but prediction of treatment outcome is not established. We investigated changes of the corticospinal tract (CST) in iNPH before and after shunt surgery by using diffusion microstructural imaging, which infers more specific tissue properties than conventional diffusion tensor imaging. Two biophysical models were used: neurite orientation dispersion and density imaging (NODDI) and white matter tract integrity (WMTI). In both methods, the orientational coherence within the CSTs was higher in patients than in controls, and some normalization occurred after the surgery in patients, indicating axon stretching and recovery. The estimated axon density was lower in patients than in controls but remained unchanged after the surgery, suggesting its potential as a marker for irreversible neuronal damage. In a Monte-Carlo simulation that represented model axons as undulating cylinders, both NODDI and WMTI separated the effects of axon density and undulation. Thus, diffusion MRI may distinguish between reversible and irreversible microstructural changes in iNPH. Our findings constitute a step towards a quantitative image biomarker that reflects pathological process and treatment outcomes of iNPH., Highlights • NODDI and WMTI provide markers of reversible and irreversible changes in iNPH. • Measures of axon orientation indicated recovery from stretching after surgery. • Axon density remained low after surgery, suggesting chronic neuronal damage. • Axon stretching in simulations differentially affected diffusion metrics.

Introduction Disproportionately Enlarged Subarachnoid space Hydrocephalus (DESH) is considered as an important imaging feature of idiopathic normal pressure hydrocephalus (iNPH). Method Subjects aged 60 and over in a memory clinic and a community-based cohort were assessed for the presence of ventriculomegaly, Sylvian dilatation, and high convexity tightness by neuroimaging, and a clinical triad of iNPH symptoms, i.e. cognitive, gait and urinary symptoms. Results In the memory clinic-based study (548 subjects), the prevalence of DESH was 1.1% and increased with age. The clinical triad was significantly more frequent in subjects with DESH (50%) compared to those with normal images (none), Sylvian dilatation (7%), and ventriculomegaly (12%). Gait disturbance was also significantly more frequent in DESH (83%) compared to those with normal images (2%), Sylvian dilatation (14%), and ventriculomegaly (26%). In the community-based cohort (946 subjects), the prevalence of DESH was 1.0% and increased with age. The clinical triad (11%) was significantly more common in subjects with DESH compared to those with normal images (none), Sylvian dilatation (2%), and ventriculomegaly (7%). Gait disturbance was also significantly more common in DESH (33%) compared to those with normal images (1%), Sylvian dilatation (4%), and ventriculomegaly (10%). Conclusion The reported prevalence of DESH was approximately 1%, and increased with age. DESH and high convexity tightness were specifically associated with the clinical triad of iNPH. Of the triad, gait disturbance was associated to DESH and high convexity tightness.

Leucine-rich-alpha-2-glykoprotein (LRG) is suggested as a potential biomarker for idiopathic normal pressure hydrocephalus (iNPH). Our goal was to compare the cerebrospinal fluid (CSF) LRG levels between 119 iNPH patients and 33 age-matched controls and with the shunt responses and the brain biopsy Alzheimer’s disease (AD) pathology among the iNPH patients. CSF LRG, Aβ1-42, P-tau181, and T-tau were measured by using commercial ELISAs. The LRG levels in the CSF were significantly increased in the iNPH patients (p &lt, 0.001) as compared to the controls, regardless of the AD pathology. However, CSF LRG did not correlate with the shunt response in contrast to the previous findings. The CSF AD biomarkers, i.e., Aβ1-42, T-tau, and P-tau correlated with the brain biopsy AD pathology as expected but were systematically lower in the iNPH patients when compared to the controls (&lt, 0.001). Our findings support that the LRG levels in the CSF are potentially useful for the diagnostics of iNPH, independent of the brain AD pathology, but contrary to previous findings, not for predicting the shunt response. Our findings also suggest a need for specific reference values of the CSF AD biomarkers for the diagnostics of comorbid AD pathology in the iNPH patients.