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Recent cohort studies on hemorrhagic and asymptomatic moyamoya disease have revealed that choroidal anastomosis, a type of fragile periventricular collateral pathway (periventricular anastomosis) typical of the disease, is an independent predictor of hemorrhagic stroke. However, treatment strategies for less-symptomatic nonhemorrhagic patients with choroidal anastomosis remain unclear. The Moyamoya Periventricular Choroidal Collateral (P-ChoC) Registry is an ongoing multicentered observational study that will test the hypothesis that extracranial-intracranial bypass prevents de novo hemorrhagic stroke in less symptomatic, nonhemorrhagic patients with choroidal anastomosis and may thus contribute to improving the prognosis of moyamoya disease. In this study, we report the study protocol of the moyamoya P-ChoC Registry and review the literature on choroidal anastomosis as a fragile collateral pathway.

Abstract Background Brain metastasis (BrM) is prevalent among patients with NSCLC, and surgical resection of BrM constitutes a promising treatment strategy for local management and histopathological diagnosis, although it is offered for a select group of patients. Limited information exists concerning the improvement in performance status (PS) following BrM resection or the outcomes stratified by subsequent systemic therapy. Methods We conducted a retrospective single-center cohort study including NSCLC patients with surgically resected BrM and focused on the improvement in PS and subsequent therapy after BrM resection. Results 71 patients were included, and the median overall survival was 18.3 months (95% confidence interval [95% CI]: 8.7, not reached). Patients with NSCLC who underwent surgical resection of BrM showed significant improvement in PS (18% and 39% showed ECOG PS of 0–1, before and after BrM resection, respectively [p = 0.006]), and patients with PS improvement were younger than those with PS unimprovement (median, 62 years versus 66 years; p = 0.041). Regarding subsequent systemic therapy after BrM resection, 21 patients (30%) received cytotoxic chemotherapy, 14 patients (20%) received tyrosine kinase inhibitors (TKIs), 3 patients (4%) received immune checkpoint inhibitors (ICIs), and 21 patients (30%) received no subsequent therapy. The survival outcomes of patients stratified by subsequent systemic treatments suggested the tendency that those who received TKI or ICI showed better survival outcomes, although a small number of patients hindered statistical comparisons. Conclusions We describe the outcomes of patients with NSCLC who underwent surgical resection of BrM, revealing that younger patients were more likely to anticipate improvement in PS, and patients who received TKI or ICI after BrM resection tended to exhibit a more preferable prognosis.

Abstract Propofol’s pharmacokinetics have been extensively studied using human blood samples and applied to target-controlled infusion systems; however, information on its concentration in the brain remains scarce. Therefore, this study aimed to simultaneously measure propofol plasma and brain concentrations in patients who underwent awake craniotomy and establish new pharmacokinetic model. Fifty-seven patients with brain tumors or brain lesions who underwent awake craniotomy were sequentially assigned to model-building and validating groups. Plasma and brain (lobectomy or uncapping margins) samples were collected at five time-points. The concentration of propofol was measured using high-performance liquid chromatography. Population pharmacokinetic analysis was conducted through a nonlinear mixed-effects modeling program using a first-order conditional estimation method with interactions. Propofol’s brain concentrations were higher than its plasma concentrations. The measured brain concentrations were higher than the effect site concentrations using the previous models. Extended models were constructed based on measured concentrations by incorporating the brain/plasma partition coefficient (Kp value). Extended models showed good predictive accuracy for brain concentrations in the validating group. The Kp value functioned as a factor explaining retention in the brain. Our new pharmacokinetic models and Kp value can predict propofol’s brain and plasma concentrations, contributing to safer and more stable anesthesia.

Abstract Recent studies have indicated the involvement of neutrophil-mediated inflammatory responses in the process leading to intracranial aneurysm (IA) rupture. Receptors mediating neutrophil recruitment could thus be therapeutic targets of unruptured IAs. In this study, complement C5a receptor 1 (C5AR1) was picked up as a candidate that may cause neutrophil-dependent inflammation in IA lesions from comprehensive gene expression profile data acquired from rat and human samples. The induction of C5AR1 in IA lesions was confirmed by immunohistochemistry; the up-regulations of C5AR1/C5ar1 stemmed from infiltrated neutrophils, which physiologically express C5AR1/C5ar1, and adventitial fibroblasts that induce C5AR1/C5ar1 in human/rat IA lesions. In in vitro experiments using NIH/3T3, a mouse fibroblast-like cell line, induction of C5ar1 was demonstrated by starvation or pharmacological inhibition of mTOR signaling by Torin1. Immunohistochemistry and an experiment in a cell-free system using recombinant C5 protein and recombinant Plasmin indicated that the ligand of C5AR1, C5a, could be produced through the enzymatic digestion by Plasmin in IA lesions. In conclusion, we have identified a potential contribution of the C5a–C5AR1 axis to neutrophil infiltration as well as inflammatory responses in inflammatory cells and fibroblasts of IA lesions. This cascade may become a therapeutic target to prevent the rupture of IAs.

Abstract This study investigated the link between pre-stroke and acute-stage physical activity (PA) and sedentary behavior. Forty individuals with stroke (aged 73.6 ± 8.9 years) were enrolled. Post-stroke activity, including metabolic equivalents (METs), sedentary behavior, light PA, and moderate-to-vigorous PA (MVPA), was measured using a tri-axial accelerometer (ActiGraph wGT3X-BT) over 11 consecutive days starting from the 4th day post-stroke. Pre-stroke PA levels were assessed using the International Physical Activity Questionnaire (IPAQ). We measured skeletal muscle mass index (SMI) and phase angle using a bioelectrical impedance analyzer (Inbody S10) upon admission. Physical therapists assessed the Brunnstrom recovery stage (BRS) within 3 days post-stroke. Total daily activity averaged 1.05 ± 0.05 METs. Throughout the day, 91.2 ± 5.1, 7.6 ± 4.1, and 1.2 ± 1.3% was spent in sedentary behavior, light PA, and MVPA, respectively. Only pre-stroke PA was independently associated with METs (β = 0.66), sedentary behavior (β = −0.58), light PA (β = 0.50), and MVPA (β = 0.71) after adjusting for age, sex, stroke severity, and activities of daily living. This suggests that pre-stroke PA might play a crucial role in reducing sedentary behavior and promoting PA during the acute phase.

Abstract Background Epilepsy is a major symptom in patients with glioma. Levetiracetam (LEV) is recognized as a first-line treatment for glioma-related epilepsy. Increasing the LEV dose is allowed into patients with seizure occurrence against its initial dose. However, the therapeutic efficacy of increasing the LEV dose in response to seizure occurrence remains unclear. Methods We retrospectively analyzed 236 glioma patients who were treated with antiseizure medications (ASMs) internally at our institute between September 2010 and December 2017. Of these, the analysis focused on 156 patients treated with LEV who had a clear history of administration. Results Seizure occurrences were observed in 21 of 75 patients (26.7%) who received LEV as first-line therapy and in 33 of 81 patients (40.7%) who received LEV as non-first-line treatment. The seizure control rate for seizure occurrence with LEV as first-line treatment was significantly higher in patients treated with addition of other ASMs (72.7%) than in those treated with increasing dose of LEV (20.0%) (p = 0.016). The seizure control rate for seizure occurrence with LEV as non-first-line treatment did not differ significantly between patients with addition of other ASMs (58.3%) and those treated with increasing dose of LEV (47.6%) (p = 0.554). Conclusions Adding other ASMs was more effective than increasing the LEV dose for seizure control in patients treated with LEV as first-line treatment, but they demonstrated comparable efficacy in patients treated with LEV as non-first-line treatment.

Cognitive impairment in adult patients with moyamoya disease (MMD) is sometimes overlooked and can occur in patients with no ischemic or hemorrhagic lesions. Better profiling and reliable diagnostic methods that characterize the group and associate the impairments and pathology of MMD are required in order to deliver appropriate treatments and support. The potential of 123I-iomazenil single-photon emission computed tomography (SPECT) for this issue has been reported in some studies, but the universality of this method remains unclear. A multicenter study of adult patients (aged 18-60 years) with MMD who experienced difficulties in social lives despite normal activities of daily living was implemented to delineate the common characteristics of this group of patients. In this study, iomazenil SPECT, besides patient characteristics, cognitive functions, and conventional imaging, was acquired to examine whether this method is suitable as a universal diagnostic tool. A total of 36 patients from 12 institutes in Japan were included in this study. Domain scores of world health organization quality of life 26 indicated low self-rating in physical health and psychological domains. The percentages of patients who had

Abstract Subarachnoid hemorrhage being the rupture of intracranial aneurysm (IA) as a major cause has quite poor prognosis, despite the modern technical advances. Thereby, the mechanisms underlying the rupture of lesions should be clarified. Recently, we and others have clarified the formation of vasa vasorum in IA lesions presumably for inflammatory cells to infiltrate in lesions as the potential histopathological alternation leading to rupture. In the present study, we clarified the origin of vasa vasorum as arteries located at the brain surface using 3D-immunohistochemistry with tissue transparency. Using Hypoxyprobe, we then found the presence of hypoxic microenvironment mainly at the adventitia of intracranial arteries where IA is formed. In addition, the production of vascular endothelial growth factor (VEGF) from cultured macrophages in such a hypoxic condition was identified. Furthermore, we found the accumulation of VEGF both in rupture-prone IA lesions induced in a rat model and human unruptured IA lesions. Finally, the VEGF-dependent induction of neovessels from arteries on brain surface was confirmed. The findings from the present study have revealed the potential role of hypoxic microenvironment and hypoxia-induced VEGF production as a machinery triggering rupture of IAs via providing root for inflammatory cells in lesions to exacerbate inflammation.

Background and purposeAlthough aneurysm shrinkage often occurs after flow diversion treatment for intracranial aneurysms, no reports have addressed the factors associated with aneurysm shrinkage.Materials and methodsThis retrospective single-center study was performed to examine patients with unruptured internal carotid artery aneurysms who were treated using flow diversion and followed up by imaging for at least 12 months. The study outcome was aneurysm shrinkage (volume reduction of ≥10%) 12 months after treatment. Aneurysm volume was quantitatively assessed using the MRIcroGL software. Patient and aneurysm characteristics were statistically analyzed.ResultsThis study involved 81 patients with 88 aneurysms. At the 6 months, 12 months, and last follow-ups, the proportion of aneurysms that had shrunk was 50, 64, and 65%, respectively. No adjunctive coiling (odds ratio, 56.7; 95% confidence interval, 7.03–457.21; p

Abstract Introduction Meningiomas are the most common primary central nervous system tumors. Predicting the grade and proliferative activity of meningiomas would influence therapeutic strategies. We aimed to apply the multiple parameters from preoperative diffusion tensor images for predicting meningioma grade and proliferative activity. Methods Nineteen patients with low‐grade meningiomas and eight with high‐grade meningiomas were included. For the prediction of proliferative activity, the patients were divided into two groups: Ki‐67 monoclonal antibody labeling index (MIB‐1 LI)

Abstract Background Detecting immunoglobulin G4 (IgG4)-related intracranial arteriopathy, a rare neurovascular complication of IgG4-related disease, is challenging. While magnetic resonance (MR) vessel wall imaging (VWI) can visualize various neurovascular pathologies, its application to this arteriopathy has not been reported as of this writing. Case presentation A 74-year-old male and a 65-year-old female manifested multiple cranial nerve palsy and neck pain, respectively. Both cases exhibited multiorgan masses with markedly elevated serum IgG4 levels and were clinically diagnosed with IgG4-related disease. Three-dimensional T1-weighted black blood VWI with and without contrast agent identified intracranial vascular lesions characterized as nearly-circumferential mural thickening with homogeneous contrast enhancement in the internal carotid and vertebral arteries; some of the lesions had been unrecognized with screening MR angiography due to expansive remodeling. The former patient underwent corticosteroid therapy, and VWI after treatment revealed decreased mural thickening and enhancement. Conclusion Further studies to elucidate characteristic findings of VWI might contribute to early detection of this treatable pathology.

Abstract The association between neurocognitive function (NCF) impairment and brain cortical functional connectivity in glioma patients remains unclear. The correlations between brain oscillatory activity or functional connectivity and NCF measured by the Wechsler Adult Intelligence Scale full-scale intelligence quotient scores (WAIS FSIQ), the Wechsler Memory Scale-revised general memory scores (WMS-R GM), and the Western aphasia battery aphasia quotient scores (WAB AQ) were evaluated in 18 patients with left frontal glioma using resting-state electroencephalography (EEG). Current source density (CSD) and lagged phase synchronization (LPS) were analyzed using exact low-resolution electromagnetic tomography (eLORETA). Although 2 and 2 patients scored in the borderline range of WAIS FSIQ and WMS-R GM, respectively, the mean WAIS FSIQ, WMS-R GM, and WAB AQ values of all patients were within normal limits, and none had aphasia. In the correlation analysis, lower WMS-R GM was associated with a higher LPS value between the right anterior prefrontal cortex and the left superior parietal lobule in the beta1 band (13–20 Hz, R = − 0.802, P = 0.012). These findings suggest that LPS evaluated by scalp EEG is associated with memory function in patients with left frontal glioma and mild NCF disorders.

Abstract Moyamoya disease (MMD) is a rare cerebrovascular disease endemic in East Asia. The p.R4810K mutation in RNF213 gene confers a risk of MMD, but other factors remain largely unknown. We tested the association of gut microbiota with MMD. Fecal samples were collected from 27 patients with MMD, 7 patients with non-moyamoya intracranial large artery disease (ICAD) and 15 control individuals with other disorders, and 16S rRNA were sequenced. Although there was no difference in alpha diversity or beta diversity between patients with MMD and controls, the cladogram showed Streptococcaceae was enriched in patient samples. The relative abundance analysis demonstrated that 23 species were differentially abundant between patients with MMD and controls. Among them, increased abundance of Ruminococcus gnavus > 0.003 and decreased abundance of Roseburia inulinivorans

Interfering with RUNX family proteins reduces glioblastoma growth in mice and reveals pathways involved in the maintenance of tumour growth.

This study aimed to measure the impact of the COVID-19 pandemic on the volumes of annual stroke admissions compared with those before the pandemic in Japan. We conducted an observational, retrospective nationwide survey across 542 primary stroke centers in Japan. The annual admission volumes for acute stroke within 7 days from onset between 2019 as the pre-pandemic period and 2020 as the pandemic period were compared as a whole and separately by months during which the epidemic was serious and prefectures of high numbers of infected persons. The number of stroke patients declined from 182,660 in 2019 to 178,083 in 2020, with a reduction rate of 2.51% (95% confidence interval [CI], 2.58%-2.44%). The reduction rates were 1.92% (95% CI, 1.85%-2.00%; 127,979-125,522) for ischemic stroke, 3.88% (95% CI, 3.70%-4.07%, 41,906-40,278) for intracerebral hemorrhage, and 4.58% (95% CI, 4.23%-4.95%; 13,020-12,424) for subarachnoid hemorrhage. The admission volume declined by 5.60% (95% CI, 5.46%-5.74%) during the 7 months of 2020 when the epidemic was serious, whereas it increased in the remaining 5 months (2.01%; 95% CI, 1.91%-2.11%). The annual decline in the admission volume was predominant in the five prefectures with the largest numbers of infected people per million population (4.72%; 95% CI, 4.53%-4.92%). In conclusion, the acute stroke admission volume declined by 2.51% in 2020 relative to 2019 in Japan, especially during the months of high infection, and in highly infected prefectures. Overwhelmed healthcare systems and infection control practices may have been associated with the decline in the stroke admission volume during the COVID-19 pandemic.

In this report, we, the Research Committee on Moyamoya Disease (Spontaneous Occlusion of the circle of Willis), describe in detail the changes in the new “Diagnostic Criteria 2021” for moyamoya disease and its scientific basis to make it widely known to the world. The revised criteria cover all aspects of the disease, including a definition of the disease concept, diagnostic imaging, and the concept of quasi-moyamoya disease (moyamoya syndrome).

Abstract Background To evaluate the impact of three risk factors (age [≥75 years], renal impairment [creatinine clearance

The number of awake craniotomies is increasing because of its beneficial features. However, not enough information is available regarding the current status of awake craniotomy in Japan. To evaluate the current status of awake craniotomy in institutes, a nationwide questionnaire survey was conducted. From June to August 2019, we conducted a questionnaire survey on awake craniotomy in the neurosurgery department of 45 institutes that perform awake craniotomies in Japan. Responses were obtained from 39 institutes (response rate, 86.7%). The main methods of awake craniotomy were almost the same in all institutes. Twenty-six institutes (66.7%) had fewer than 10 awake craniotomies (low-volume institutes) per year, and 13 high-volume institutes (33.3%) performed more than 10 awake craniotomies annually. Some institutes experienced a relatively high frequency of adverse events. In 11 institutes (28.2%), the frequency of intraoperative seizures was more than 10%. An intraoperative seizure frequency of 1%-9%, 10%-29%, and over 30% was identified in 12 (92%), 0 (0%), and 1 (8%) of the high-volume institutes, which was significantly less than in 16 (62%), 10 (38%), and 0 (0%) of the low-volume institutes (p = 0.0059). The routine usage of preoperative antiepileptic drugs was not different between them, but the old type was used more often in the low-volume institutes (p = 0.0022). Taken together, the annual number of awake craniotomies was less than 10 in over two-thirds of the institutes. Fewer intraoperative seizures were reported in the high-volume institutes, which tend not to preoperatively use the old type of antiepileptic drugs.

Abstract The role of the bifurcation angle in progression of saccular intracranial aneurysms (sIAs) has been undetermined. We, therefore, assessed the association of bifurcation angles with aneurysm progression using a bifurcation-type aneurysm model in rats and anterior communicating artery aneurysms in a multicenter case–control study. Aneurysm progression was defined as growth by ≥ 1 mm or rupture during observation, and controls as progression-free for 30 days in rats and ≥ 36 months in humans. In the rat model, baseline bifurcation angles were significantly wider in progressive aneurysms than in stable ones. In the case–control study, 27 and 65 patients were enrolled in the progression and control groups. Inter-observer agreement for the presence or absence of the growth was excellent (κ coefficient, 0.82; 95% CI, 0.61–1.0). Multivariate logistic regression analysis showed that wider baseline bifurcation angles were significantly associated with subsequent progressions. The odds ratio for the progression of the second (145°–179°) or third (180°–274°) tertiles compared to the first tertile (46°–143°) were 5.5 (95% CI, 1.3–35). Besides, the bifurcation angle was positively correlated with the size of aneurysms (Spearman’s rho, 0.39; P = 0.00014). The present study suggests the usefulness of the bifurcation angle for predicting the progression of sIAs.

Objectives To examine the national, 6-year trends in in-hospital clinical outcomes of patients with subarachnoid haemorrhage (SAH) who underwent clipping or coiling and the prognostic influence of temporal trends in the Comprehensive Stroke Center (CSC) capabilities on patient outcomes in Japan.Design Retrospective study.Setting Six hundred and thirty-one primary care institutions in Japan.Participants Forty-five thousand and eleven patients with SAH who were urgently hospitalised, identified using the J-ASPECT Diagnosis Procedure Combination database.Primary and secondary outcome measures Annual number of patients with SAH who remained untreated, or who received clipping or coiling, in-hospital mortality and poor functional outcomes (modified Rankin Scale: 3–6) at discharge. Each CSC was assessed using a validated scoring system (CSC score: 1–25 points).Results In the overall cohort, in-hospital mortality decreased (year for trend, OR (95% CI): 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)). The proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5%, while that of those who received coiling and those left untreated gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively. In-hospital mortality of coiled (0.94 (0.89 to 0.98)) and untreated (0.93 (0.90 to 0.96)) patients decreased, whereas that of clipped patients remained stable. CSC score improvement was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)) but not with short-term patient outcomes regardless of treatment modality.Conclusions The 6-year trends indicated lower in-hospital mortality for patients with SAH (attributable to better outcomes), increased use of coiling and multidisciplinary care for untreated patients. Further increasing CSC capabilities may improve overall outcomes, mainly by increasing the use of coiling. Additional studies are necessary to determine the effect of confounders such as aneurysm complexity on outcomes of clipped patients in the modern endovascular era.

Abstract Although cognitive impairment is well-documented in children with moyamoya disease (MMD), selective decline in specific neurocognitive domains remains controversial. The purpose of this study was to characterize the neurocognitive profile of children with MMD using the Das Naglieri Cognitive Assessment System (CAS) and the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV). We analyzed the neurocognitive data of 30 children (median age, 7 years) with MMD who were assessed with the CAS and the WISC-IV before surgery. We focused on the comparison of standard scores and intraindividual differences across domains. The CAS scores significantly varied across four measures (standard scores, p

Abstract To determine whether increasing thrombectomy-capable hospitals with moderate comprehensive stroke center (CSC) capabilities is a valid alternative to centralization of those with high CSC capabilities. This retrospective, nationwide, observational study used data from the J-ASPECT database linked to national emergency medical service (EMS) records, captured during 2013–2016. We compared the influence of mechanical thrombectomy (MT) use, the CSC score, and the total EMS response time on the modified Rankin Scale score at discharge among patients with acute ischemic stroke transported by ambulance, in phases I (2013–2014, 1461 patients) and II (2015–2016, 3259 patients). We used ordinal logistic regression analyses to analyze outcomes. From phase I to II, MTs increased from 2.7 to 5.5%, and full-time endovascular physicians per hospital decreased. The CSC score and EMS response time remained unchanged. In phase I, higher CSC scores were associated with better outcomes (1-point increase, odds ratio [95% confidence interval]: 0.951 [0.915–0.989]) and longer EMS response time was associated with worse outcomes (1-min increase, 1.007 [1.001–1.013]). In phase II, neither influenced the outcomes. During the transitional shortage of thrombectomy-capable hospitals, increasing hospitals with moderate CSC scores may increase nationwide access to MT, improving outcomes.

Abstract Background Intra-cranial schwannomas account for less than 8% of brain tumors, among which more than 80% arise from the vestibular nerve. Intra-cerebellar schwannomas are extremely rare. Several cases have been previously reported but without remarkable degenerative changes on histology. Case presentation A 61-year-old man presented with worsening disorientation, and an imaging study revealed a cystic lesion (6.5 cm in the largest diameter) in the left hemisphere of the cerebellum accompanied by a mural nodule (2.5 cm) located just inside the skull with enhancement and focal calcification, in addition to hydrocephalus. The lesion was more than 5 mm from the left acoustic nerve. The patient underwent gross total resection. Pathological examination revealed remarkable degenerative changes with various morphological features. Tumor cells were pleomorphic with rich cytoplasm containing numerous eosinophilic granules. Blood vessels and extracellular matrix showed remarkable hyalinization. Immunohistochemical staining revealed that the tumor cells were positive for S-100 protein and negative for Olig2. The tumor was diagnosed as a schwannoma with marked degenerative changes. Conclusions The present case is discussed with reference to a systematic review of previous reports of intra-cerebellar schwannoma. Intra-cerebellar schwannoma should be included in the differential diagnosis of cystic lesions with heterogeneous histopathological morphology in the cerebellum.

Abstract Awake craniotomy enables mapping and monitoring of brain functions. For successful procedures, rapid awakening and the precise evaluation of consciousness are required. A prospective, observational study conducted to test whether intraoperative hand strength could be a sensitive indicator of consciousness during the awake phase of awake craniotomy. Twenty-three patients who underwent awake craniotomy were included. Subtle changes of the level of consciousness were assessed by the Japan Coma Scale (JCS). The associations of hand strength on the unaffected side with the predicted plasma concentration (Cp) of propofol, the bispectral index (BIS), and the JCS were analyzed. Hand strength relative to the preoperative maximum hand strength on the unaffected side showed significant correlations with the Cp of propofol (ρ = − 0.219, p = 0.007), the BIS (ρ = 0.259, p = 0.002), and the JCS (τ = − 0.508, p = 0.001). Receiver operating characteristic curve analysis for discriminating JCS 0–1 and JCS ≥ 2 demonstrated that the area under the curve was 0.76 for hand strength, 0.78 for Cp of propofol, and 0.66 for BIS. With a cutoff value of 75% for hand strength, the sensitivity was 0.76, and the specificity was 0.67. These data demonstrated that hand strength is a useful indicator for assessing the intraoperative level of consciousness during awake craniotomy.

Prophet of Pit1 (PROP1) is the pituitary specific transcription factor which was cloned as an upstream regulator of PIT1. Cushing’s disease is caused by corticotroph adenomas which does not belong to the PIT1 lineage. The aim of this study was to elucidate the involvement of PROP1 in the pathogenesis of Cushing’s disease. Since it is difficult to accurately evaluate PROP1 expression in pituitary adenomas by RT-PCR analysis due to the inevitable contamination of surgical tissue specimens with normal pituitary cells, we examined six corticotroph adenomas by immunohistochemistry. Adenomas were classified into 2 subtypes based on their staining patterns of CAM5.2: diffuse and non-diffuse types. It is likely that diffuse-type adenomas are composed of more differentiated tumor cells. PROP1 was positive in all three cases of non-diffuse-type adenomas, but negative in all three cases of diffuse-type adenomas, suggesting that PROP1 was prominently expressed in less differentiated non-PIT1 lineage corticotroph adenomas. This study is the first report to analyze PROP1 expression in pituitary adenomas by immunohistochemistry. PROP1 may have a role in tumorigenesis of pituitary adenomas in Cushing’s disease, and is expected to be a new therapeutic target for refractory pituitary adenomas.

Anti-vascular endothelial growth factor (VEGF) therapy has been developed for the treatment of a variety of cancers. Although this therapy may be a promising alternative treatment for refractory pituitary adenomas and pituitary carcinomas, the effects of anti-VEGF agents on the pituitary gland are not yet well understood. Here, we found that mice administered with OSI-930, an inhibitor of receptor tyrosine kinases including VEGF receptor 1 and 2, frequently exhibited hemorrhage in the pituitary gland. This is the first report that anti-VEGF therapy can cause pituitary apoplexy. C57BL/6 mice were daily injected intraperitoneally with 100 mg/kg body weight of OSI-930 for one to six days. Pituitary glands were immunohistochemically examined. Four of six mice treated for three days and all of five mice treated for six days exhibited hemorrhage in the pituitary gland. In all cases, the hemorrhage occurred just around Rathke's cleft. In OSI-930-administered mice, the vascular coverage and branching were reduced in the anterior lobe, and capillary networks were also decreased in the intermediate lobe in a treatment-day dependent manner. Few blood vessels around Rathke's cleft of the intermediate lobe express VE-cadherin and are covered with platelet-derived growth factor receptor-β (PDGFR-β)-positive cells, which suggests that capillaries around Rathke's cleft of the intermediate lobe were VE-cadherin-negative and not covered with pericytes. The reduction of capillary plexus around Rathke's cleft was observed at the site where hemorrhage occurred, suggesting a causal relationship with the pathogenesis of pituitary hemorrhage. Our study demonstrates that anti-VEGF agents have a risk of pituitary apoplexy. Pituitary apoplexy should be kept in mind as an adverse effect of anti-VEGF therapy.

The medial parietal cortices are components of the default mode network (DMN), which are active in the resting state. The medial parietal cortices include the precuneus and the dorsal posterior cingulate cortex (dPCC). Few studies have mentioned differences in the connectivity in the medial parietal cortices, and these differences have not yet been precisely elucidated. Electrophysiological connectivity is essential for understanding cortical function or functional differences. Since little is known about electrophysiological connections from the medial parietal cortices in humans, we evaluated distinct connectivity patterns in the medial parietal cortices by constructing a standardized connectivity map using cortico-cortical evoked potential (CCEP). This study included nine patients with partial epilepsy or a brain tumor who underwent chronic intracranial electrode placement covering the medial parietal cortices. Single-pulse electrical stimuli were delivered to the medial parietal cortices (38 pairs of electrodes). Responses were standardized using the z-score of the baseline activity, and a response density map was constructed in the Montreal Neurological Institutes (MNI) space. The precuneus tended to connect with the inferior parietal lobule (IPL), the occipital cortex, superior parietal lobule (SPL), and the dorsal premotor area (PMd) (the four most active regions, in descending order), while the dPCC tended to connect to the middle cingulate cortex, SPL, precuneus, and IPL. The connectivity pattern differs significantly between the precuneus and dPCC stimulation (p

Abstract Background Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas. Methods This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis. Results RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology. Conclusion RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma.

Abstract The characteristics of IDH-wild-type lower-grade astrocytoma remain unclear. According to cIMPACT-NOW update 3, IDH-wild-type astrocytomas with any of the following factors show poor prognosis: combination of chromosome 7 gain and 10 loss (+ 7/− 10), and/or EGFR amplification, and/or TERT promoter (TERTp) mutation. Multiplex ligation-dependent probe amplification (MLPA) can detect copy number alterations at reasonable cost. The purpose of this study was to identify a precise, cost-effective method for stratifying the prognosis of IDH-wild-type astrocytoma. Sanger sequencing, MLPA, and quantitative methylation-specific PCR were performed for 42 IDH-wild-type lower-grade astrocytomas surgically treated at Kyoto University Hospital, and overall survival was analysed for 40 patients who underwent first surgery. Of the 42 IDH-wild-type astrocytomas, 21 were classified as grade 4 using cIMPACT-NOW update 3 criteria and all had either TERTp mutation or EGFR amplification. Kaplan–Meier analysis confirmed the prognostic significance of cIMPACT-NOW criteria, and World Health Organization grade was also prognostic. Cox regression hazard model identified independent significant prognostic indicators of PTEN loss (risk ratio, 9.75; p

Abstract Background Removal of large hypervascular tumors in the lateral ventricle still poses a surgical challenge. These tumors are usually fed from choroidal arteries, and vascular control is typically performed late during the removal. We aimed to evaluate the clinical efficacy of our strategy for persistent preoperative obliteration of feeders from the choroidal arteries to manage large hypervascular tumors in the lateral ventricle. Methods We retrospectively analyzed six patients with hypervascular tumors in the lateral ventricle. We first attempted to obstruct feeders using endovascular treatment, and, if unavailable, performed initial microsurgical occlusion through the temporal horn for the staged tumor removal. Results In all patients, feeder obliteration was successfully performed; the anterior choroidal arteries were occluded by the endovascular treatment and microsurgical occlusion in one and five patients, respectively, while the lateral posterior choroidal arteries were occluded via endovascular treatment in four patients. No patients had permanent symptoms due to feeder obliteration, and tumor devascularization was achieved at the mean rate of 69.9%. During the tumor removal, the mean blood loss volume was 253 ml. No postoperative hemorrhage had occurred, and all patients scored ≤ 2 on the modified Rankin Scale at six months post-removal. Conclusions Although further studies are warranted, persistent feeder obliteration of choroidal arteries could be an effective treatment strategy against large hypervascular tumors in the lateral ventricle.

White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

Abstract Background Despite rapid developments in devices used to treat arteriovenous malformation (AVM), a randomised trial of Unruptured Brain Arteriovenous malformations published in 2014 recommended conservative treatment for nonhemorrhagic AVM. The purpose of the current retrospective study was to confirm how AVM treatment in Japan has changed and to assess the safety of treatment for hemorrhagic and nonhemorrhagic AVMs. Methods We enrolled 242 consecutive patients with AVM; each patient’s treatment was selected and performed at our hospital. The type of onset, Spetzler–Martin (S–M) grade, age, sex, selected treatment, mortality, and morbidity were compared between the first and second periods of our study. Results In patients with grade I–III AVM, the selected treatment changed between the first and second periods; however, in grade IV and V patients, the selected treatment did not change. Overall, interventions by microsurgery alone decreased (p

Abstract Background As subarachnoid hemorrhage due to rupture of an intracranial aneurysm (IA) has quite a poor outcome despite of an intensive medical care, development of a novel treatment targeting unruptured IAs based on the correct understanding of pathogenesis is mandatory for social health. Methods Using previously obtained gene expression profile data from surgically resected unruptured human IA lesions, we selected G-protein coupled receptor 120 (GPR120) as a gene whose expression is significantly higher in lesions than that in control arterial walls. To corroborate a contribution of GPR120 signaling to the pathophysiology, we used an animal model of IAs and examine the effect of a GPR120 agonist on the progression of the disease. IA lesion was induced in rats through an increase of hemodynamic stress achieved by a one-sided carotid ligation and induced hypervolemia. Eicosapentaenoic acid (EPA) was used as an agonist for GPR120 in this study and its effect on the size of IAs, the thinning of media, and infiltration of macrophages in lesions were examined. Result EPA administered significantly suppressed the size of IAs and the degenerative changes in the media in rats. EPA treatment also inhibited infiltration of macrophages, a hallmark of inflammatory responses in lesions. In in vitro experiments using RAW264.7 cells, pre-treatment of EPA partially suppressed lipopolysaccharide-induced activation of nuclear factor-kappa B and also the transcriptional induction of monocyte chemoattractant protein 1 (MCP-1), a major chemoattractant for macrophages to accumulate in lesions. As a selective agonist of GPR120, TUG-891, could reproduce the effect of EPA in RAW264.7 cells, EPA presumably acted on this receptor to suppress inflammatory responses. Consistently, EPA remarkably suppressed MCP-1 expression in lesions, suggesting the in vivo relevance of in vitro studies. Conclusions These results combined together suggest the potential of the medical therapy targeting GPR120 or using EPA to prevent the progression of IAs.

How does the human brain encode semantic information about objects? This paper reconciles two seemingly contradictory views. The first proposes that local neural populations independently encode semantic features; the second, that semantic representations arise as a dynamic distributed code that changes radically with stimulus processing. Combining simulations with a well-known neural network model of semantic memory, multivariate pattern classification, and human electrocorticography, we find that both views are partially correct: information about the animacy of a depicted stimulus is distributed across ventral temporal cortex in a dynamic code possessing feature-like elements posteriorly but with elements that change rapidly and nonlinearly in anterior regions. This pattern is consistent with the view that anterior temporal lobes serve as a deep cross-modal ‘hub’ in an interactive semantic network, and more generally suggests that tertiary association cortices may adopt dynamic distributed codes difficult to detect with common brain imaging methods.

Background The optimal duration of dual antiplatelet therapy (DAPT) in patients with cerebral aneurysm who undergo stent-assisted coil embolization (SACE) has not been established. We aimed to clarify the association between duration of DAPT and incidence of ischemic stroke in patients with cerebral aneurysm. Methods We registered patients with cerebral aneurysm who underwent SACE in 27 hospitals in Japan. Those treated with DAPT (aspirin and clopidogrel) were eligible for inclusion in a previously reported randomized control trial (RCT). Patients who were ineligible or refused to participate to the RCT were followed-up for 15 months after SACE as the non-RCT cohort. Our study examined both the RCT and non-RCT cohorts. The primary and secondary outcomes were ischemic stroke and hemorrhagic events. Results Among the 313 patients registered, 296 were included for analysis (of these, 136 were RCT patients and 160 were non-RCT patients). Patients who were treated with DAPT for more than 6 months (n=191) were classified as the long-term DAPT group. Those treated less than 6 months (n=105) were classified as the short-term group. The incidence of ischemic stroke did not significantly differ between the long-term group (2.5 per 100 person-years) and the short-term group (3.2 per 100 person-years); nor did incidence of hemorrhagic events (0.8 and 3.2 per 100 person-years, respectively). The period of DAPT was not significantly associated with incidence rates of ischemic stroke or hemorrhagic events. Conclusions Duration of DAPT was not associated with the incidence of ischemic stroke in the first 15 months after SACE. [ABSTRACT FROM AUTHOR]

Moyamoya disease is an idiopathic chronically progressive cerebrovascular disease, which causes both ischemic and hemorrhagic stroke. Genetic studies identified RNF213/Mysterin and GUCY1A3 as disease-causing genes. They were also known to be associated with non-moyamoya intracranial large artery disease, coronary artery disease and pulmonary artery hypertension. This review focused on these two molecules and their strong linker, calcineurin/NFAT signaling and caveolin to understand the pathophysiology of moyamoya disease and related vascular diseases. They are important regulators of lipid metabolism especially lipotoxicity, NF-κB mediated inflammation, and nitric oxide-mediated vascular protection. Although intimal thickening with fibrosis and damaged vascular smooth muscle cells are the distinguishing features of moyamoya disease, origin of the fibrous tissue and the mechanism of smooth muscle cell damages remains not fully elucidated. Endothelial cells and smooth muscle cells have long been a focus of interest, but other vascular components such as immune cells and extracellular matrix also need to be investigated in future studies. Molecular research on moyamoya disease would give us a clue to understand the mechanism preserving vascular stability.

To preserve postoperative brain function, it is important for neurosurgeons to fully understand the brain's structure, vasculature, and function. Intraoperative high-frequency electrical stimulation during awake craniotomy is the gold standard for mapping the function of the cortices and white matter; however, this method can only map the “focal” functions and cannot monitor large-scale cortical networks in real-time. Recently, an in vivo electrophysiological method using cortico-cortical evoked potentials (CCEPs) induced by single-pulse electrical cortical stimulation has been developed in an extraoperative setting. By using the CCEP connectivity pattern intraoperatively, mapping and real-time monitoring of the dorsal language pathway is available. This intraoperative CCEP method also allows for mapping of the frontal aslant tract, another language pathway, and detection of connectivity between the primary and supplementary motor areas in the frontal lobe network. Intraoperative CCEP mapping has also demonstrated connectivity between the frontal and temporal lobes, likely via the ventral language pathway. Establishing intraoperative electrophysiological monitoring is clinically useful for preserving brain function, even under general anesthesia. This CCEP technique demonstrates potential clinical applications for mapping and monitoring large-scale cortical networks.

BackgroundThe Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) was designed to investigate safety and effectiveness during long-term follow-up of rivaroxaban treatment, using reduced doses compared with other global regions, in Japanese patients with non-valvular atrial fibrillation in real-world clinical practice.MethodsIn this prospective, open-label, single-arm, observational study, 11,308 patients with non-valvular atrial fibrillation newly prescribed rivaroxaban (15/10 mg once daily) at 1416 sites across Japan were enrolled and followed for a mean of 2.5 years.ResultsIn total, 10,664 and 10,628 patients were included in the safety and effectiveness analyses, respectively. In the safety population, mean (standard deviation) age was 73.1 (9.8) years and Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, previous Stroke/TIA (2 points) (CHADS2) score was 2.2 (1.3). Incidences (95% confidence intervals) of any and major bleeding were 3.77 (3.53-4.01) and 1.16 (1.03-1.29) events per 100 patient-years, respectively. Age ≥75 years, creatinine clearance ConclusionIn the XAPASS, a large-scale study involving a broad range of patients with non-valvular atrial fibrillation newly prescribed rivaroxaban using Japan-specific dosage in real-world clinical practice, no unexpected safety or effectiveness concerns were detected during up to 5 years of follow-up.

Background and purposeEstablishment of drug therapy to prevent rupture of unruptured intracranial aneurysms (IAs) is needed. Previous human and animal studies have gradually clarified candidate drugs for preventive treatment of IA rupture. However, because most of these candidates belong to classes of drugs frequently co-administered to prevent cardiovascular diseases, epidemiological studies evaluating these drugs simultaneously should be performed. Furthermore, because drugs included in the same class may have different effects in terms of disease prevention, drug-by-drug assessments are important for planning intervention trials.Materials and methodsWe performed a cross-sectional study enrolling patients diagnosed with IAs between July 2011 and June 2019 at our institution. Patients were divided into ruptured or unruptured groups. The drugs investigated were selected according to evidence suggested by either human or animal studies. Univariate and multivariate logistic regression analyses were performed to assess the association of drug treatment with rupture status. We also performed drug-by-drug assessments of the association, including dose-response relationships, with rupture status.ResultsIn total, 310 patients with ruptured and 887 patients with unruptured IAs were included. Multivariate analysis revealed an inverse association of statins (odds ratio (OR), 0.54; 95% confidence interval (CI) 0.38-0.77), calcium channel blockers (OR, 0.41; 95% CI 0.30-0.58), and angiotensin II receptor blockers (ARBs) (OR, 0.67; 95% CI 0.48-0.93) with ruptured IAs. Moreover, inverse dose-response relationships with rupture status were observed for pitavastatin and rosuvastatin among statins, benidipine, cilnidipine, and amlodipine among calcium channel blockers, and valsartan, azilsartan, candesartan, and olmesartan among ARBs. Only non-aspirin non-steroidal anti-inflammatory drugs were positively associated with ruptured IAs (OR, 3.24; 95% CI 1.71-6.13).ConclusionsThe present analysis suggests that several types of statins, calcium channel blockers, and ARBs are candidate drugs for preventive treatment of unruptured IAs.

Background and objectiveIt has long been believed that the bony carotid canal has no plasticity and that a small canal represents a hypoplastic internal carotid artery. We aimed to show whether the carotid canal can narrow according to morphological changes in the internal carotid artery.Materials and methodsThe carotid canal diameter was longitudinally measured in seven individuals who underwent carotid artery ligation. As moyamoya disease is known to be associated with negative remodeling of the internal carotid artery, the carotid canal diameter was measured in 106 patients with moyamoya disease, and an association with the outer diameter of the internal carotid artery or a correlation with the disease stage was investigated. The carotid canal was measured by computed tomography (106 patients), and the outer diameter of the artery was measured by high-resolution magnetic resonance imaging (63 patients). The carotid canal area was calculated by the product of the maximum axial diameter and its perpendicular diameter.ResultsAll seven patients who underwent carotid artery ligation showed narrowing of the carotid canal, and the carotid canal area decreased by 12.2%-28.9% during a mean follow-up period of 4.2 years. In patients with moyamoya disease, the carotid canal area showed a linear correlation with the outer area of the internal carotid artery (r = 0.657, p < 0.001), and a negative correlation with the disease stage (ρ = -0.283, p < 0.001).ConclusionThe bony carotid canal has plasticity, and its area reflects the outer area of the internal carotid artery, therefore, it can be used to assess the remodeling of the carotid artery. A narrow carotid canal may not necessarily indicate hypoplastic internal carotid artery.

Background Decreased extracellular matrix formation and few vascular smooth muscle cells (VSMCs) in cerebral vascular walls are the main characteristics of intracranial aneurysm (IA) pathogenesis. Recently, osteoprotegerin was reported to activate collagen biosynthesis and VSMC proliferation via the TGF‐β1 (transforming growth factor‐β1) signaling. This study aimed to investigate whether osteoprotegerin can prevent IA progression in rats through enhanced collagen expression and VSMC proliferation. Methods and Results IAs were surgically induced in 7‐week‐old male Sprague–Dawley rats; at 1‐week post‐operation, recombinant mouse osteoprotegerin or vehicle control was continuously infused for 4 weeks into the lateral ventricle using an osmotic pump. In the osteoprotegerin‐treatment group, the aneurysmal size was significantly smaller (37.5 μm versus 60.0 μm; P

Background Carotid plaques with expansive arterial remodeling are closely related to cerebral ischemic events. Although S100A4 (S100 calcium‐binding protein A4) is expressed in atherosclerotic lesions, its role in atherosclerotic plaque progression remains unknown. In this study, we examined the association between carotid arterial expansive remodeling and S100A4 expression. Methods and Results Preoperative high‐resolution magnetic resonance imaging was used to assess luminal stenosis and vascular remodeling in patients undergoing carotid endarterectomy. To examine murine carotid atherosclerosis, we induced experimental lesions by flow cessation in apolipoprotein E‐deficient mice fed a high‐fat diet. The role of S100A4 in plaque formation and smooth muscle cell proliferation was investigated in vivo and in vitro, respectively. Human carotid arterial expansive remodeling showed positive correlations with the expression of S100A4, MMP2, and MMP9. S100A4 mRNA levels were positively correlated with those of MMP2, MMP9, and MMP13. S100A4 was expressed in vascular smooth muscle cells (VSMCs) and VSMC‐derived foam cells in the plaque shoulder and marginal areas. S100A4 expression increased concomitantly with plaque formation in our animal model. Exogenous recombinant S100A4 protein enhanced the levels of Mmp2, Mmp9, and Mmp13 and the cell proliferation ability in VSMCs. A chemotaxis assay indicated that extracellular S100A4 functions as a chemoattractant for VSMCs. Conclusions S100A4 expression was elevated in human carotid plaques and showed a positive correlation with the degree of expansive remodeling. S100A4‐positive VSMC‐derived cells are considered to play an important role in carotid expansive remodeling.

Background and PurposeChronic inflammation is involved in the formation and enlargement of cerebral aneurysms (CAs), with macrophages playing a key role in the process. The present study evaluated visualization of macrophages present in CAs using an activatable fluorescent probe (IONP-ICG) comprising an iron oxide nanoparticles (IONPs) conjugated with indocyanine green (ICG).MethodsIONP-ICG was intravenously administered to 15-week-old CA model rats (n = 8), and ex vivo near-infrared fluorescence (NIRF) imaging and histological assessment of exposed CAs and cerebral arteries were performed 48 h later. Similar evaluations were performed in the control group, which included CA model rats given IONPs or ICG (n = 8 each).ResultsICG-derived NIRF signals were detected in three IONP-ICG group rats but not in IONP or ICG control groups. Among the three rats that exhibited signals, NIRF signal accumulation was observed in the CA of two rats and at the site of hemodynamic stress in the left posterior cerebral artery in one rat. Histologically, NIRF signals correlated strongly with macrophage localization. A total of 13 CAs formed in the IONP-ICG group. The number of macrophages in the CA wall was significantly greater in the two CAs that exhibited NIRF signals compared to the remaining 11 CAs that did not (P = 0.037). Moreover, all 11 CAs that did not exhibit NIRF signals were iron-negative, while the two CAs that exhibited NIRF signals were both iron-positive (P = 0.013).ConclusionNIRF imaging using an activatable IONP-ICG probe is feasible for detecting the macrophage-rich regions in CAs and the cerebral artery wall, which is considered an early lesion in the process of CA formation.

Abstract Background The phase III Japanese Rivaroxaban Once‐Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (J‐ROCKET AF) showed that the rivaroxaban group had a lower event rate of intracranial bleeding than the warfarin group and that rivaroxaban was noninferior to warfarin for the principal safety outcome. However, safety and effectiveness data from unselected patients with AF in everyday clinical practice in Japan are lacking. Methods The Xarelto Post‐Authorization Safety & Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) is a real‐world, prospective, single‐arm, observational study mandated by the Japanese authority as postmarketing surveillance. XAPASS involves patients with nonvalvular AF prescribed rivaroxaban. The principal safety outcome is a composite of major and nonmajor bleeding events, and the primary effectiveness outcome is the incidence of ischemic stroke, hemorrhagic stroke, noncentral nervous system systemic embolism, and myocardial infarction. Results In total, 11 308 patients were enrolled from April 2012 to June 2014. Their age was 73.1 ± 9.9 years, and their CHADS2 score was 2.2 ± 1.3. Female patients, patients aged ≥75 years, patients with a body weight of ≤50 kg, and patients with a creatinine clearance of