Enlarged Perivascular Space and Index for Diffusivity Along the Perivascular Space as Emerging Neuroimaging Biomarkers of Neurological Diseases.

The existence of lymphatic vessels or similar clearance systems in the central nervous system (CNS) that transport nutrients and remove cellular waste is a neuroscientific question of great significance. As the brain is the most metabolically active organ in the body, there is likely to be a potential correlation between its clearance system and the pathological state of the CNS. Until recently the successive discoveries of the glymphatic system and the meningeal lymphatics solved this puzzle. This article reviews the basic anatomy and physiology of the glymphatic system. Imaging techniques to visualize the function of the glymphatic system mainly including post-contrast imaging techniques, indirect lymphatic assessment by detecting increased perivascular space, and diffusion tensor image analysis along the perivascular space (DTI-ALPS) are discussed. The pathological link between glymphatic system dysfunction and neurological disorders is the key point, focusing on the enlarged perivascular space (EPVS) and the index of diffusivity along the perivascular space (ALPS index), which may represent the activity of the glymphatic system as possible clinical neuroimaging biomarkers of neurological disorders. The pathological link between glymphatic system dysfunction and neurological disorders is the key point, focusing on the enlarged perivascular space (EPVS) and the index for of diffusivity along the perivascular space (ALPS index), which may represent the activity of the glymphatic system as possible clinical neuroimaging biomarkers of neurological disorders.

Clinical features and outcomes of pediatric intracranial gliomas: results from single center's 226 cases and corroborated with SEER database.

BACKGROUND: Pediatric gliomas are the most common central nervous system (CNS) tumors in children and adolescents and show different clinical and histopathological characteristics from the adult. The prognostic factors were poorly defined in pediatric intracranial gliomas. METHODS: We collected pediatric intracranial glioma cases in our institution between February 2011 and June 2022. The patient clinical data, tumor growth characteristics, treatments, and follow-up data were analyzed by Cox regression analysis to identify impact factors on the prognosis of pediatric intracranial glioma patients. To corroborate our data, an independent cohort of pediatric intracranial glioma from the Surveillance, Epidemiology, and End Results Program (SEER) database was analyzed. RESULTS: A total of 181 cases of pediatric low-grade glioma (PLGG) and 45 cases of pediatric high-grade glioma (PHGG) were included. In multivariate Cox regression analysis, tumor size > 59.5 mm (p = 0.006) and non-gross total resection (non-GTR; subtotal resection, STR, p = 0.042; biopsy, p = 0.012) were associated with decreased overall survival (OS) in PLGG patients. In PHGG patients, only chemotherapy (p = 0.023) was associated with OS while tumor size was marginally prognostic for OS (p = 0.051). Additional independent analysis of 2734 PLGG and 741 PHGG from the SEER database corroborated that larger tumor size was associated with decreased OS in LGG (p = 0.001) and HGG (p < 0.001) patients, separately. CONCLUSION: In this study, we found that tumor size was a significant prognostic factor for the OS of PLGG patients in our series. Besides the tumor size, the extent of resection also independently impacted the prognosis of PLGG patients. While in PHGG patients, only chemotherapy was associated with improved OS and tumor size was marginally prognostic.

Growing and symptomatic intracranial arachnoid cyst in an elderly patient: a case report and literature review.

We report an elderly patient with a symptomatic and growing arachnoid cyst. Physician should be cautious in counseling asymptomatic arachnoid cyst patients, regardless of their age, and inform them of the possibility, although rare, of growth and symptom development even in their late life.

The GBM Tumor Microenvironment as a Modulator of Therapy Response: ADAM8 Causes Tumor Infiltration of Tams through HB-EGF/EGFR-Mediated CCL2 Expression and Overcomes TMZ Chemosensitization in Glioblastoma.

Standard chemotherapy of Glioblastoma multiforme (GBM) using temozolomide (TMZ) frequently fails due to acquired chemoresistance. Tumor-associated macrophages and microglia (TAMs) as major immune cell population in the tumor microenvironment are potential modulators of TMZ response. However; little is known about how TAMs participate in TMZ induced chemoresistance. Members of the metzincin superfamily such as Matrix Metalloproteases (MMPs) and A Disintegrin and Metalloprotease (ADAM) proteases are important mediators of cellular communication in the tumor microenvironment. A qPCR screening was performed to identify potential targets within the ADAM and MMP family members in GBM cells. In co-culture with macrophages ADAM8 was the only signature gene up-regulated in GBM cells induced by macrophages under TMZ treatment. The relationship between ADAM8 expression and TAM infiltration in GBM was determined in a patient cohort by qPCR; IF; and IHC staining and TCGA data analysis. Moreover; RNA-seq was carried out to identify the potential targets regulated by ADAM8. CCL2 expression levels were determined by qPCR; Western blot; IF; and ELISA. Utilizing qPCR; IF; and IHC staining; we observed a positive relationship between ADAM8 expression and TAMs infiltration level in GBM patient tissues. Furthermore; ADAM8 induced TAMs recruitment in vitro and in vivo. Mechanistically; we revealed that ADAM8 activated HB-EGF/EGFR signaling and subsequently up-regulated production of CCL2 in GBM cells in the presence of TMZ treatment; promoting TAMs recruitment; which further induced ADAM8 expression in GBM cells to mediate TMZ chemoresistance. Thus; we revealed an ADAM8 dependent positive feedback loop between TAMs and GBM cells under TMZ treatment which involves CCL2 and EGFR signaling to cause TMZ resistance in GBM.

TGFBI secreted by tumor-associated macrophages promotes glioblastoma stem cell-driven tumor growth via integrin αvß5-Src-Stat3 signaling.

Rationale: In the glioblastoma (GBM) microenvironment, tumor-associated macrophages (TAMs) are prominent components and facilitate tumor growth. The exact molecular mechanisms underlying TAMs' function in promoting glioma stem cells (GSCs) maintenance and tumor growth remain largely unknown. We found a candidate molecule, transforming growth factor beta-induced (TGFBI), that was specifically expressed by TAMs and extremely low in GBM and GSC cells, and meanwhile closely related to glioma WHO grades and patient prognosis. The exact mechanism of TGFBI linking TAM functions to GSC-driven tumor growth was explored. Methods: Western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), immunohistochemistry staining (IHC) and public datasets were used to evaluate TGFBI origin and level in GBM. The response of GSCs to recombinant human TGFBI was assessed in vitro and orthotopic xenografts were established to investigate the function and mechanism in vivo. Results: M2-like TAMs infiltration was elevated in high-grade gliomas. TGFBI was preferentially secreted by M2-like TAMs and associated with a poor prognosis for patients with GBM. TGFBI promoted the maintenance of GSCs and GBM malignant growth through integrin αvß5-Src-Stat3 signaling in vitro and in vivo. Of clinical relevance, TGFBI was enriched in the serum and CSF of GBM patients and significantly decreased after tumor resection. Conclusion: TAM-derived TGFBI promotes GSC-driven tumor growth through integrin αvß5-Src-Stat3 signaling. High serum or CSF TGFBI may serve as a potential diagnostic and prognostic bio-index for GBMs.

Signal Pathways Involved in the Interaction Between Tumor-Associated Macrophages/TAMs and Glioblastoma Cells.

It is commonly recognized, that glioblastoma is a large complex composed of neoplastic and non-neoplastic cells. Tumor-associated macrophages account for the majority of tumor bulk and play pivotal roles in tumor proliferation, migration, invasion, and survival. There are sophisticated interactions between malignant cells and tumor associated-macrophages. Tumor cells release a variety of chemokines, cytokines, and growth factors that subsequently lead to the recruitment of TAMs, which in return released a plethora of factors to construct an immunosuppressive and tumor-supportive microenvironment. In this article, we have reviewed the biological characteristics of glioblastoma-associated macrophages and microglia, highlighting the emerging molecular targets and related signal pathways involved in the interaction between TAMs and glioblastoma cells, as well as the potential TAMs-associated therapeutic targets for glioblastoma.

Investigating Causal Relationships Between Psychiatric Traits and Intracranial Aneurysms: A Bi-directional Two-Sample Mendelian Randomization Study.

Background Despite psychiatric traits were associated with intracranial aneurysms (IAs) in observational studies, their causal relationships remain largely undefined. We aimed to assess the causality between psychiatric traits and IAs. Methods We firstly collected the genome-wide association statistics of IAs (sample size, n = 79,429) and ten psychiatric traits from Europeans, including insomnia (n = 1,331,010), mood instability (n = 363,705), anxiety disorder (n = 83,566), major depressive disorder (MDD) (n = 480,359), subjective wellbeing (n = 388,538), attention deficit/hyperactivity disorder (ADHD) (n = 53,293), autism spectrum disorder (ASD) (n = 46,350), bipolar disorder (BIP) (n = 51,710), schizophrenia (SCZ) (n = 105,318), and neuroticism (n = 168,105). We then conducted a series of bi-directional two-sample Mendelian randomization (MR) analyses, of which the Robust Adjusted Profile Score (RAPS) was the primary method to estimate the causal effects between these psychiatric traits and IAs. Results We found that insomnia exhibited a significant risk effect on IAs with the odds ratio (OR) being 1.22 (95% CI: 1.11-1.34, p = 4.61 × 10-5) from the RAPS method. There was suggestive evidence for risk effect of mood instability on IAs (RAPS, OR = 4.16, 95% CI: 1.02-17.00, p = 0.047). However, no clear evidence of causal effects on IAs for the rest eight psychiatric traits (anxiety disorder, MDD, subjective wellbeing, ADHD, ASD, BIP, SCZ, and neuroticism) was identified. In the reverse MR analyses, no causal effects of IAs on psychiatric traits were found. Conclusions Our findings provide strong evidence for a causal risk effect of insomnia on IAs and suggestive evidence for mood instability as a causal risk effect on IAs. These results could inform the prevention and clinical intervention of IAs.

Surgical fenestration might not be the best option for very young patients with middle fossa arachnoid cysts.

PURPOSE: Surgical fenestration is widely accepted as a primary treatment for middle fossa arachnoid cysts (MFACs) in pediatric patients. However, postoperative subdural effusion and/or hydrocephalus always affect treatment outcomes. In this study, we presented our experience of treating MFACs with surgical fenestration in pediatric patients and analyzed the cases complicated by postoperative subdural effusion and/or hydrocephalus, to give insight into the clinical characteristics predisposing the complications. METHODS: We retrospectively analyzed 21 pediatric cases with MFACs treated by surgical fenestration suffering postoperative subdural effusion and/or hydrocephalus in our department from November 2011 to April 2019. We reviewed the clinical characteristics and treatment outcomes. RESULTS: A total of 21 patients, among a total of 53 pediatric patients with MFACs treated by surgical fenestration, developed subdural effusion and/or hydrocephalus postoperatively. The mean age at the time of the initial surgery was 49 months. A total of 75% (6/8) of the patients under 2 years old and 13.3% (6/45) of the older patient group sustaining postoperative subdural effusion and/or hydrocephalus required further surgeries, respectively (Fisher's exact test, p = 0.001). Notably, among the 21 cases with postoperative subdural effusion and/or hydrocephalus, all the 6 patients under 2 years old needed additional surgeries, while of the other 15 older patients, only 40% (6/15) needed further surgical interventions (Fisher's exact test, p = 0.019). CONCLUSION: The immature CSF absorption in MFAC patients younger than 2 years old might predispose them to the relatively serious postoperative subdural effusion and/or hydrocephalus. For very young patients with giant MFACs, surgical fenestration might not be the best option.

Exploiting tumor-intrinsic signals to induce mesenchymal stem cell-mediated suicide gene therapy to fight malignant glioma.

BACKGROUND: Human mesenchymal stem cell (MSC)-based tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene delivery is regarded as an effective treatment for glioblastoma (GBM). However, adverse-free target site homing of the delivery vehicles to the tumor microsatellite nests is challenging, leading to erroneously sustained released of this suicide protein into the normal brain parenchyma; therefore, limiting off-target cytotoxicity and controlled expression of the suicide inductor is a prerequisite for the safe use of therapeutic stem cells. METHODS: Utilizing the intrinsic expression profile of GBM and its elevated expression of TGF-ß relative to normal brain tissue, we sought to engineer human adipose-derived MSCs (hAMSC-SBE4-TRAIL) which augment the expression of TRAIL under the trigger of TGF-ß signaling. We validated our therapeutic technology in a series of functional in vitro and in vivo assays using primary patient-derived GBM models. RESULTS: Our current findings show that these biologic delivery vehicles have high tumor tropism efficacy and expression TRAIL gene under the trigger of TGF-ß-secreting GBMs, as well as avoid unspecific TRAIL secretion into normal brain tissue. hAMSC-SBE4-TRAIL inhibited the proliferation and induced apoptosis in experimental GBMs both in vitro and in vivo. In addition, our improved platform of engineered MSCs significantly decreased the tumor volume and prolonged survival time in a murine model of GBM. CONCLUSIONS: Our results on the controlled release of suicide inductor TRAIL by exploiting an endogenous tumor signaling pathway demonstrate a significant improvement for the clinical utility of stem cell-mediated gene delivery to treat brain cancers. Harvesting immune-compatible MSCs from patients' fat by minimally invasive procedures further highlights the clinical potential of this approach in the vision of applicability in a personalized manner. The hAMSC-SBE4-TRAIL exhibit great curative efficacy and are a promising cell-based treatment option for GBM to be validated in clinical exploration.

Shunt Dependency Syndrome after Cyst-Peritoneal Shunt Resolved by Keyhole Microsurgical Cyst Resection: Two Case Reports and Literature Review.

OBJECTIVE: Shunt dependency syndrome after cyst-peritoneal (CP) shunt is a rare but serious complication which leads to increased intracranial pressure and neurological deficit. The possible mechanism still remains in controversy. We present our experience on the treatment of the complication and attempt to find a better therapy strategy for the complication. METHODS: Two children with middle fossa arachnoid cysts underwent CP shunt with fixed pressure catheters at an opening pressure of 7 cmH2O and then developed dependency syndrome. Both patients were effectively treated by mini-invasive cyst wall excision with the shunts reserved. The clinical manifestation, radiological findings, treatment methods, and therapeutic outcomes were reviewed retrospectively. RESULTS: The time from shunt surgery to shunt dependency syndrome occurrence was 4 and 2 years, respectively. Computed tomography/magnetic resonance findings of the brain showed remarkably collapsed cysts with normal or small ventricles. Both patients underwent secondary mini-invasive cyst wall excision and shunt catheters were reserved. After the operations, their symptoms were resolved except one case with marginally improved visual impairment. CONCLUSION: Shunt dependency syndrome is a rare but dangerous complication of CP shunt and should be treated in time. Collapsed and thickened cyst wall intermittent covering the catheter head end, decreased brain compliance due to chronic fibrosis, as well as regression of cerebrospinal fluid absorption could be the pathogenesis. We suggest keyhole resection of the residual cyst wall as an effective and mini-invasive treatment option.

Macroinvertebrate communities and the relationships with biotic factors in river-connected lakes in the lower reaches of Yangtze River, China.

The relationships of macroinvertebrate communities with abiotic factors in lake and river system were well documented, but their relationships with biotic factors were few explored. The macroinvertebrate communities in two river-disconnected lakes (Poyang Lake and Shijiu Lake) and the rivers connected to Shijiu Lake were investigated to reveal the differences in communities and explore the relationships with biotic factors. A total of 34 species were recorded in the three water bodies. Combined with the previous study results, the dominant species in Poyang Lake is almost unchanged since 1997. Mollusks were dominated in abundance in Poyang Lake and the rivers connected to Shijiu Lake, while oligochaetes dominated the communities in Shijiu Lake. The alpha diversity indices of macroinvertebrates in Poyang Lake and the rivers connected to Shijiu Lake were distinctly higher than that of Shijiu Lake, and the beta diversity index of Shijiu Lake was the highest, supporting the rules that alpha diversity of macroinvertebrates achieves a maximum at a moderate level of connectivity and beta diversity seems to be higher when the connectivity is weaker. The differences in communities were significant between the Poyang Lake and Shijiu Lake, while the differences in the Poyang Lake and the rivers connected to Shijiu Lake were not significant. According to the results of canonical correspondence analysis (CCA), protozoon densities and phytoplankton biomass affected the distribution of macroinvertebrates in Shijiu Lake. Species number of planktonic crustaceans influenced the distribution of macroinvertebrates in rivers connected to Shijiu Lake, while species number of rotifer and densities of phytoplankton distinctly impacted on the distribution of macroinvertebrates in Poyang Lake.

Air-water CO2 outgassing in the Lower Lakes (Alexandrina and Albert, Australia) following a millennium drought.

Lakes are an important source and sink of atmospheric CO2, and thus are a vital component of the global carbon cycle. However, with scarce data on potentially important subtropical and tropical areas for whole continents such as Australia, the magnitude of large-scale lake CO2 emissions is unclear. This study presents spatiotemporal changes of dissolved inorganic carbon and water - to - air interface CO2 flux in the two of Australia's largest connected, yet geomorphically different freshwater lakes (Lake Alexandrina and Lake Albert, South Australia), during drought (2007 to September-2010) and post-drought (October 2010 to 2013). Lake levels in the extreme drought were on average approximately 1m lower than long-term average (0.71 m AHD). Drought was associated with an increase in the concentrations of dissolved inorganic species, organic carbon, nitrogen, Chl-a and major ions, as well as water acidification as a consequence of acid sulfate soil (ASS) exposure, and hence, had profound effects on lake pCO2 concentrations. Lakes Alexandrina and Albert were a source of CO2 to the atmosphere during the drought period, with efflux ranging from 0.3 to 7.0 mmol/m(2)/d. The lake air-water CO2 flux was negative in the post-drought, ranging between -16.4 and 0.9 mmol/m(2)/d. The average annual CO2 emission was estimated at 615.5×10(6) mol CO2/y during the drought period. These calculated emission rates are in the lower range for lakes, despite the potential for drought conditions that shift the lakes from sink to net source for atmospheric CO2. These observations have significant implications in the context of predicted increasing frequency and intensity of drought as a result of climate change. Further information on the spatial and temporal variability in CO2 flux from Australian lakes is urgently warranted to revise the global carbon budget for lakes.

The metalloprotease-disintegrin ADAM8 contributes to temozolomide chemoresistance and enhanced invasiveness of human glioblastoma cells.

BACKGROUND: Despite multimodal treatment, glioblastoma (GBM) therapy with temozolomide (TMZ) remains inefficient due to chemoresistance. Matrix metalloproteinase (MMP) and a disintegrin and metalloprotease (ADAM), increased in GBM, could contribute to chemoresistance and TMZ-induced recurrence of glioblastoma. METHODS: TMZ inducibility of metalloproteases was determined in GBM cell lines, primary GBM cells, and tissues from GBM and recurrent GBM. TMZ sensitivity and invasiveness of GBM cells were assessed in the presence of the metalloprotease inhibitors batimastat (BB-94) and marimastat (BB-2516). Metalloprotease-dependent effects of TMZ on mitochondria and pAkt/phosphatidylinositol-3 kinase (PI3K) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) pathways were analyzed by fluorescence activated cell sorting, morphometry, and immunoblotting. Invasiveness of GBM cells was determined by Matrigel invasion assays. Potential metalloprotease substrates were identified by proteomics and tested for invasion using blocking antibodies. RESULTS: TMZ induces expression of MMP-1, -9, -14, and ADAM8 in GBM cells and in recurrent GBM tissues. BB-94, but not BB-2516 (ADAM8-sparing) increased TMZ sensitivity of TMZ-resistant and -nonresistant GBM cells with different O(6)-methylguanine-DNA methyltransferase states, suggesting that ADAM8 mediates chemoresistance, which was confirmed by ADAM8 knockdown, ADAM8 overexpression, or pharmacological inhibition of ADAM8. Levels of pAkt and pERK1/2 were increased in GBM cells and correlated with ADAM8 expression, cell survival, and invasiveness. Soluble hepatocyte growth factor (HGF) R/c-met and CD44 were identified as metalloprotease substrates in TMZ-treated GBM cells. Blocking of HGF R/c-met prevented TMZ-induced invasiveness. CONCLUSIONS: ADAM8 causes TMZ resistance in GBM cells by enhancing pAkt/PI3K, pERK1/2, and cleavage of CD44 and HGF R/c-met. Specific ADAM8 inhibition can optimize TMZ chemotherapy of GBM in order to prevent formation of recurrent GBM in patients.