Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system
. These highly diverse and ...specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and temporally restricted subclasses of microglia in the central nervous system during development or disease. Here we combine massively parallel single-cell analysis, single-molecule fluorescence in situ hybridization, advanced immunohistochemistry and computational modelling to comprehensively characterize subclasses of microglia in multiple regions of the central nervous system during development and disease. Single-cell analysis of tissues of the central nervous system during homeostasis in mice revealed specific time- and region-dependent subtypes of microglia. Demyelinating and neurodegenerative diseases evoked context-dependent subtypes of microglia with distinct molecular hallmarks and diverse cellular kinetics. Corresponding clusters of microglia were also identified in healthy human brains, and the brains of patients with multiple sclerosis. Our data provide insights into the endogenous immune system of the central nervous system during development, homeostasis and disease, and may also provide new targets for the treatment of neurodegenerative and neuroinflammatory pathologies.
In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient treatment success is, in large parts, ...due to the tremendous molecular heterogeneity of gliomas, which affects the overall prognosis and response to therapies and plays a vital role in gliomas’ grading. In addition, the tumor microenvironment is a major player for glioma development and resistance to therapy. Active communication between glioma cells and local or neighboring healthy cells and the immune environment promotes the cancerogenic processes and contributes to establishing glioma stem cells, which drives therapy resistance. Besides genetic alterations in the primary tumor, tumor-released factors, cytokines, proteins, extracellular vesicles, and environmental influences like hypoxia provide tumor cells the ability to evade host tumor surveillance machinery and promote disease progression. Moreover, there is increasing evidence that these players affect the molecular biological properties of gliomas and enable inter-cell communication that supports pro-cancerogenic cell properties. Identifying and characterizing these complex mechanisms are inevitably necessary to adapt therapeutic strategies and to develop novel measures. Here we provide an update about these junctions where constant traffic of biomolecules adds complexity in the management of glioblastoma.
Graphical abstract
Cavernous vascular malformations occur with a frequency of 1:200 and can cause recurrent headaches, seizures and hemorrhagic stroke if located in the brain. Familial cerebral cavernous malformations ...(CCMs) have been associated with germline mutations in CCM1/KRIT1, CCM2 or CCM3/PDCD10. For each of the three CCM genes, we here show complete localized loss of either CCM1, CCM2 or CCM3 protein expression depending on the inherited mutation. Cavernous but not adjacent normal or reactive endothelial cells of known germline mutation carriers displayed immunohistochemical negativity only for the corresponding CCM protein but not for the two others. In addition to proving loss of function at the protein level, our data are the first to demonstrate endothelial cell mosaicism within cavernous tissues and provide clear pathogenetic evidence that the endothelial cell is the cell of disease origin.
Abstract
Brain tumors are typically immunosuppressive and refractory to immunotherapies for reasons that remain poorly understood. The unbiased profiling of immune cell types in the tumor ...microenvironment may reveal immunologic networks affecting therapy and course of disease. Here we identify and validate the presence of hematopoietic stem and progenitor cells (HSPCs) within glioblastoma tissues. Furthermore, we demonstrate a positive link of tumor-associated HSPCs with malignant and immunosuppressive phenotypes. Compared to the medullary hematopoietic compartment, tumor-associated HSPCs contain a higher fraction of immunophenotypically and transcriptomically immature, CD38- cells, such as hematopoietic stem cells and multipotent progenitors, express genes related to glioblastoma progression and display signatures of active cell cycle phases. When cultured ex vivo, tumor-associated HSPCs form myeloid colonies, suggesting potential in situ myelopoiesis. In experimental models, HSPCs promote tumor cell proliferation, expression of the immune checkpoint PD-L1 and secretion of tumor promoting cytokines such as IL-6, IL-8 and CCL2, indicating concomitant support of both malignancy and immunosuppression. In patients, the amount of tumor-associated HSPCs in tumor tissues is prognostic for patient survival and correlates with immunosuppressive phenotypes. These findings identify an important element in the complex landscape of glioblastoma that may serve as a target for brain tumor immunotherapies.
ABSTRACT
BACKGROUND
Delayed cerebral ischemia (DCI) has a strong impact on outcome of patients with aneurysmal subarachnoid hemorrhage (SAH). Positive effect of antiplatelet therapy on DCI rates has ...been supposed upon smaller SAH series.
OBJECTIVE
To analyze the benefit/risk profile of antiplatelet use in SAH patients.
METHODS
This retrospective case–control study was based on institutional observational cohort with 994 SAH patients treated between January 2003 and June 2016. The individuals with postcoiling antiplatelet therapy (aspirin with/without clopidogrel) were compared to a control group without antiplatelet therapy. Occurrence of DCI, major/minor bleeding events in the follow-up computed tomography scans, and favorable outcome at 6 mo after SAH (modified Rankin scale < 3) were compared in both groups.
RESULTS
Of 580 patients in the final analysis, 329 patients received post-treatment antiplatelet medication. There were no significant differences between the compared groups with regard to basic outcome confounders. Aspirin use was independently associated with reduced DCI risk (P < .001, adjusted odds ratio = 0.41, 95% confidence interval 0.24-0.65) and favorable outcome (P = .02, adjusted odds ratio = 1.78, 95% confidence interval 1.06-2.98). Regarding bleeding complications, aspirin was associated only with minor bleeding events (P = .02 vs P = .51 for major bleeding events).
CONCLUSION
Regular administration of aspirin might have a positive impact on DCI risk and outcome of SAH patients, without increasing the risk for clinically relevant bleeding events. In our SAH cohort, dual antiplatelet therapy showed no additional benefit on DCI risk, but increased the likelihood of major bleeding events.
Blood pressure management is crucial in the treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). Possible association between the blood pressure increase and the risk of delayed ...cerebral ischemia (DCI) and different systemic complications after aSAH is still a matter of debate. This study aims to elucidate the influence of blood pressure levels on the outcome of aSAH. All consecutive aSAH patients (n = 690) treated between 01/2003 and 06/2016 were included. The mean value of the mean arterial pressure (MAP) during 14 days after ictus was calculated for each individual. According to the institutional standards of vasospasm management, the mean 14 days MAP ≥ 95 mmHg was referred as increased (IMAP) and the patients with and without vasospasm were analyzed separately. Study endpoints were the occurrence of DCI on computed tomography scans, development of cardiac and nephrological complications, and poor outcome 6 months after aSAH (mRS > 2). Associations were tested in univariable/multivariable binary logistic regression analysis. IMAP was documented in 474 (68.7%) cases and was more common in individuals with poor neurological conditions at admission (p < 0.001), severe amount of intracranial blood (p = 0.001) and premorbid hypertension (p < 0.001). IMAP was independently associated with the occurrence of DCI (p = 0.014; aOR = 2.97; 95% CI 1.25-7.09) and poor functional outcome (p = 0.020; aOR = 3.14; 95% CI 1.20-8.22) in patients with vasospasm, but not in counterparts without vasospasm (p = 0.113/p = 0.086). IMAP had no influence on cardiac or nephrological complications. In aSAH individuals with cerebral vasospasm, sustained increase of blood pressure exceeding the therapeutic targets is strongly associated with the risk of DCI and poor outcome. Therefore, such an intrinsic increase of blood pressure might reflect the autoregulatory mechanisms against the impending cerebral ischemia in patients with cerebral vasospasm.Trial registration number: German clinical trial registry (DRKS, Unique identifier: DRKS00008749, 06/09/2015).
Animal models are still indispensable for understanding the basic principles of glioma development and invasion. Preclinical approaches aim to analyze the treatment efficacy of new drugs before ...translation into clinical trials is possible. Various animal disease models are available, but not every approach is useful for addressing specific questions. In recent years, it has become increasingly evident that the tumor microenvironment plays a key role in the nature of glioma. In addition to providing an overview, this review evaluates available rodent models in terms of usability for research on the glioma microenvironment.
OBJECTIVE The complete clipping of a cerebral aneurysm usually warrants its sustained occlusion, while clip remnants may have far-reaching consequences. The aim of this study is to identify the risk ...factors for clip remnants requiring retreatment and/or exhibiting growth. METHODS All consecutive patients with primary aneurysm clipping performed at University Hospital of Essen between January 1, 2003, and December 31, 2013, were eligible for this study. Aneurysm occlusion was judged on obligatory postoperative digital subtraction angiography and the need for repeated vascular control. The identified clip remnants were correlated with various demographic and clinical characteristics of the patients, aneurysm features, and surgery-related aspects. RESULTS Of 616 primarily clipped aneurysms, postoperative angiography revealed 112 aneurysms (18%) with clip remnants requiring further control (n = 91) or direct retreatment (n = 21). Seven remnants exhibited growth during follow-up, whereas 2 cases were associated with aneurysmal bleeding. Therefore, a total of 28 aneurysms (4.5%) were retreated as clip remnants (range 1 day to 67 months after clipping). In the multivariate analysis, the need for retreatment of clip remnant was correlated with the aneurysm's initial size (> 12 mm; OR 3.22; p = 0.035) and location (anterior cerebral artery > internal carotid artery > posterior circulation > middle cerebral artery; OR 1.85; p = 0.003). Younger age with a cutoff at 45 years (OR 33.31; p = 0.004) was the only independent predictor for remnant growth. CONCLUSIONS The size and location of the aneurysm are the main risk factors for clip remnants requiring retreatment. Because of the risk for growth, younger individuals (< 45 years old) with clip remnants require a long-term (> 5 years) vascular follow-up. Clinical trial registration no: DRKS00008749 (Deutsches Register Klinischer Studien).
The partial pressure of carbon dioxide (PaCO2) in the arterial blood is a strong vasomodulator affecting cerebral blood flow and the risk of cerebral edema and ischemia after acute brain injury. In ...turn, both complications are related to poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). We aimed to analyze the effect of PaCO2 levels on the course and outcome of aSAH. All patients of a single institution treated for aSAH over 13.5 years were included (n = 633). Daily PaCO2 values from arterial blood gas measurements were recorded for up to 2 weeks after ictus. The study endpoints were: delayed cerebral ischemia (DCI), need for decompressive craniectomy due to increased intracranial pressure > 20 mmHg refractory to conservative treatment and poor outcome at 6-months follow-up (modified Rankin scale > 2). By correlations with the study endpoints, clinically relevant cutoffs for the 14-days mean values for the lowest and highest daily PaCO2 levels were defined by receiver operating characteristic curve analysis. Association with the study endpoints for the identifies subgroups was analyzed using multivariate analysis. The optimal range for PaCO2 values was identified between 30 and 38 mmHg. ASAH patients with poor initial condition (WFNS 4/5) were less likely to show PaCO2 values within the range of 30-38 mmHg (p < 0.001, OR = 0.44). In the multivariate analysis, PaCO2 values between 30 and 38 mmHg were associated with a lower risk for decompressive craniectomy (p = 0.042, aOR = 0.27), DCI occurrence (p = 0.035; aOR = 0.50), and poor patient outcome (p = 0.004; aOR = 0.42). The data from this study shows an independent positive association between low normal mean PaCO2 values during the acute phase of aSAH and patients' outcome. This effect might be attributed to the reduction of intracranial hypertension and alterations in the cerebral blood flow.
The quantity of ultra-high field MRI neuroimaging studies has rapidly increased. This study tests function, safety, and image artifacts of two frequently implanted programmable ventriculo-peritoneal ...(VP) shunt valves in a 7T MRI system. All tests were performed using a whole-body 7T MRI system. Three proGAV 2.0 and 3 CODMAN CERTAS® Plus programmable VP-shunt valves were tested in three steps. 1) Deflection angle tests close to the bore opening at the location of a static magnetic field gradient of 3-5 T/m. 2) Valves were fixed on a spherical phantom in 3 positions (a. lateral, b. cranial, c. cranial with 22.5° tilt anteriorly) and assessed for keeping the programmed pressure setting and reprogrammability. 3) Valves were fixed on the phantom and positioned lateral in a radiofrequency head coil. MRI scans were performed for both models, including MPRAGE, GRE and SE sequences. Deflection angles were moderate (13°, 14°, 13°) for the proGAV valves and close to critical (43°, 43°, 41°) for the CODMAN valves at the test location. Taking a scaling factor of 2-3 for the maximum spatial magnetic field gradient accessible to a patient within the magnet bore into account renders both valves MR unsafe regarding ferromagnetic attraction. The proGAV valves kept the pressure settings in all positions and were reprogrammable in positions a. and b. In position c., reprogrammability was lost. The CODMAN valves changed their pressure setting and reprogrammability was lost in all positions. MR image signal homogeneity was unaltered in the phantom center, artifacts limit the assessability of structures in close vicinity to the valves. Both tested programmable VP-shunt valves are MR unsafe for 7T systems. Novel programming mechanisms using permanent magnets with sufficient magnetic coercivity or magnet-free mechanisms may allow the development of programmable VP-shunt valves that are conditional for 7T MR systems.
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