Microglia are tissue-resident macrophages of the CNS that orchestrate local immune responses and contribute to several neurological and psychiatric diseases. Little is known about human microglia and ...how they orchestrate their highly plastic, context-specific adaptive responses during pathology. Here we combined two high-dimensional technologies, single-cell RNA-sequencing and time-of-flight mass cytometry, to identify microglia states in the human brain during homeostasis and disease. This approach enabled us to identify and characterize a previously unappreciated spectrum of transcriptional states in human microglia. These transcriptional states are determined by their spatial distribution, and they further change with aging and brain tumor pathology. This description of multiple microglia phenotypes in the human CNS may open promising new avenues for subset-specific therapeutic interventions.
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.
Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological brain processes, including neurodegeneration. Here we characterize microglia morphology and ...transcriptional programs across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, whereas human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents compared with primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer’s and Parkinson’s disease. Our study provides an essential resource of conserved and divergent microglia pathways across evolution, with important implications for future development of microglia-based therapies in humans.
Display omitted
•Microglia single-cell expression and morphology across 450 million years of evolution•Microglia express a conserved core program, including CNS ligand-receptors pairs•Human microglia show significant heterogeneity in comparison with all mammals•Identification of disease-associated microglia gene expression modules in humans
Single-cell sequencing of microglia across evolutionary timescales leads to definition of a conserved core expression program and identification of heterogeneity in human microglia lacking in other species.
We propose a histopathological classification system for hippocampal cell loss in patients suffering from mesial temporal lobe epilepsies (MTLE). One hundred and seventy-eight surgically resected ...specimens were microscopically examined with respect to neuronal cell loss in hippocampal subfields CA1-CA4 and dentate gyrus. Five distinct patterns were recognized within a consecutive cohort of anatomically well-preserved surgical specimens. The first group comprised hippocampi with neuronal cell densities not significantly different from age matched autopsy controls no mesial temporal sclerosis (no MTS); n = 34, 19%. A classical pattern with severe cell loss in CA1 and moderate neuronal loss in all other subfields excluding CA2 was observed in 33 cases (19%), whereas the vast majority of cases showed extensive neuronal cell loss in all hippocampal subfields (n = 94, 53%). Due to considerable similarities of neuronal cell loss patterns and clinical histories, we designated these two groups as MTS type 1a and 1b, respectively. We further distinguished two atypical variants characterized either by severe neuronal loss restricted to sector CA1 (MTS type 2; n = 10, 6%) or to the hilar region (MTS type 3, n = 7, 4%). Correlation with clinical data pointed to an early age of initial precipitating injury (IPI < 3 years) as important predictor of hippocampal pathology, i.e. MTS type 1a and 1b. In MTS type 2, IPIs were documented at a later age (mean 6 years), whereas in MTS type 3 and normal appearing hippocampus (no MTS) the first event appeared beyond the age of 13 and 16 years, respectively. In addition, postsurgical outcome was significantly worse in atypical MTS, especially MTS type 3 with only 28% of patients having seizure relief after 1-year follow-up period, compared to successful seizure control in MTS types 1a and 1b (72 and 73%). Our classification system appears suitable for stratifying the clinically heterogeneous group of MTLE patients also with respect to postsurgical outcome studies.
OBJECTIVE An asymmetry of the A
segments (A1SA) of the anterior cerebral arteries (ACAs) is an assumed risk factor for the development of anterior communicating artery aneurysms (ACoAAs). It is ...unknown whether A1SA is also clinically relevant after aneurysm rupture. The authors of this study investigated the impact of A1SA on the clinical course and outcome of patients with aneurysmal subarachnoid hemorrhage (SAH). METHODS The authors retrospectively analyzed data on consecutive SAH patients treated at their institution between January 2005 and December 2012. The occurrence and severity of cerebral infarctions in the ACA territories were evaluated on follow-up CT scans up to 6 weeks after SAH. Moreover, the risk for an unfavorable outcome (defined as > 3 points on the modified Rankin Scale) at 6 months after SAH was assessed. RESULTS A total of 594 patients were included in the final analysis. An A1SA was identified on digital subtraction angiography studies from 127 patients (21.4%) and was strongly associated with ACoAA (p < 0.0001, OR 13.7). An A1SA independently correlated with the occurrence of ACA infarction in patients with ACoAA (p = 0.047) and in those without an ACoAA (p = 0.015). Among patients undergoing ACoAA coiling, A1SA was independently associated with the severity of ACA infarction (p = 0.023) and unfavorable functional outcome (p = 0.045, OR = 2.4). CONCLUSIONS An A1SA is a common anatomical variation in SAH patients and is strongly associated with ACoAA. Moreover, the presence of A1SA independently increases the likelihood of ACA infarction. In SAH patients undergoing ACoAA coiling, A1SA carries the risk for severe ACA infarction and thus an unfavorable outcome. Clinical trial registration no.: DRKS00005486 ( http://www.drks.de/ ).
Petroclival meningioma (PCM) remains a major neurosurgical challenge. There are still controversial strategic treatment concepts about surgical approach, the extent of resection, and postoperative ...radiotherapy. We aimed to evaluate prognostic factors influencing the progression-free survival (PFS) rates of PCM, with a particular focus on the retrosigmoidal approach, the role of the extent of resection, and postoperative radiotherapy.
Eighty-nine patients with complete follow-up data were included. All patients were operated on
a retrosigmoidal approach, of whom 19 underwent gross total resection (GTR) and 70 underwent subtotal resection (STR). In the subgroups of tumors with infiltration of the cavernous sinus, 41 patients received near total resection (NTR) and 24 STR. Thirty-one patients received postoperative radiotherapy of the residual tumor and 58 were treated with surgery alone. Kaplan-Meier analyses and Cox regression were used to identify significant factors associated with treatment.
GTR (
=0.0107) and postoperative radiotherapy (
=0.014) were associated with significantly improved PFS. Even the subgroup analysis of extended PCM with infiltration of the cavernous sinus (CS) showed an advantage for PFS after near total resection (NTR) (
=0.0017). The additional radiotherapy of the residual tumor in the CS in this subgroup also showed a beneficial effect on PFS (
=0.012).
The extension of surgical resection remains the most important prognostic factor in relation to oncological outcomes. However, the GTR of extended PCM with infiltration of the CS is associated with significant neurological morbidity and requires additional adjuvant therapy concepts. Postoperative radiotherapy is an important element in the treatment of the residual tumor after surgery.
Spheno-orbital meningiomas (SOM) are rare intracranial tumors that arise at the sphenoid wing. These tumors can invade important neurovascular structures making radical resection difficult, while ...residual tumors often lead to recurrence. The purpose of this study was to evaluate prognostic factors influencing the recurrence and progression-free survival (PFS) rates of spheno-orbital meningiomas, with a particular focus on the role of surgery and postoperative radiotherapy.
Between 2000 and March 2020, 65 cases of spheno-orbital meningioma were included, of which 50 cases underwent surgical treatment alone, and 15 cases underwent resection and radiotherapy. A Kaplan-Meier analysis was performed to provide median point estimates and PFS rates; further, Cox regression analysis was used to identify significant factors associated with treatment.
Gross total resection significantly reduced the risk of recurrence (p-value = 0.0062). There was no significant benefit for progression-free survival after postoperative radiotherapy (p-value = 0.42). Additionally, spheno-orbital meningiomas with an invasion of the cavernous sinus and intraconal invasion showed significantly worse PFS compared to other locations (p-value = 0.017).
The maximal safe resection remains the most important prognostic factor associated with lower recurrence rates and longer PFS in patients with spheno-orbital meningioma. The invasion of the cavernous sinus and intraconal invasion was an independent factor associated with worse PFS. Patients with postoperative high-precision radiotherapy did not show significantly better PFS due to the small number of patients.
Abstract Background context The relatively new technique of Piezosurgery is based on microvibrations, generated by the piezoelectrical effect, which results in selective bone cutting with ...preservation of adjacent soft tissue. Purpose To study the applicability of Piezosurgery in anterior cervical discectomy with fusion (ACDF) surgery. Study design/setting Prospective clinical study at the neurosurgical department of the University of Freiburg, Germany. Patient sample Nine patients with cervical disc herniation and retrovertebral osteophytes who underwent ACDF surgery. Outcome measures Piezosurgery was evaluated with respect to practicability, safety, preciseness of bone cutting, and preservation of adjacent neurovascular tissue. Pre- and postoperative clinical and radiological data were assessed. Methods Piezosurgery was supportively used in ACDF in nine patients with either radiculopathy or myelopathy from disc herniation or ventral osteophytes. After discectomy, osteophytes were removed with Piezosurgery to decompress the spinal canal and the foramina. Angled inserts were used, allowing for cutting even retrovertebral osteophytes. Results In all nine cases, Piezosurgery cut bone selectively with no damage to nerve roots, dura, or posterior longitudinal ligament. None of the patients experienced any new neurological deficit after the operation. The handling of the instrument was safe and the cut precise. Osteophytic spurs, even retrovertebral ones that generally only can be approached via corpectomies, could be safely removed because of the angled inserts through the disc space. Currently, a slightly prolonged operation time was observed for Piezosurgery. Furthermore, the design of the handpiece could be further improved to facilitate the intraoperative handling in ACDF. Conclusions Piezosurgery proved to be a useful and safe technique for selective bone cutting and removal of osteophytes with preservation of neuronal and soft tissue in ACDF. In particular, the angled inserts were effective in cutting bone spurs behind the adjacent vertebra which cannot be reached with conventional rotating burs.
To establish a practical risk chart for prediction of delayed cerebral infarction (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) by using information that is available until day 5 after ictus.
...We assessed all consecutive patients with aSAH admitted to our service between September 2008 and September 2015 (
= 417). The data set was randomly split into thirds. Two-thirds were used for model development and one-third was used for validation. Characteristics that were present between the bleeding event and day 5 (i.e., prior to >95% of DCI diagnoses) were assessed to predict DCI by using logistic regression models. A simple risk chart was established and validated.
The amount of cisternal and ventricular blood on admission CT (
), early
(i.e., mean flow velocity of either intracranial artery >160 cm/s until day 5), and a simplified binary
score until day 5 were the strongest predictors of DCI. A model combining these predictors delivered a high predictive accuracy the area under the receiver operating characteristic (AUC) curve of 0.82, Nagelkerke's
0.34 in the development cohort. Validation of the model demonstrated a high discriminative capacity with the AUC of 0.82, Nagelkerke's
0.30 in the validation cohort.
Adding level of consciousness and sonographic vasospasm between admission and postbleed day 5 to the initial blood amount allows for simple and precise prediction of DCI. The suggested risk chart may prove useful for selection of appropriate candidates for interventions to prevent DCI.
PDF
