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Cell Reports Mar 2023Tuberculous meningitis (TBM) is the most severe and deadly manifestation of tuberculosis. Neurological complications are observed in up to 50% of patients affected....
Tuberculous meningitis (TBM) is the most severe and deadly manifestation of tuberculosis. Neurological complications are observed in up to 50% of patients affected. Here, attenuated Mycobacterium bovis are injected into the cerebellum of mice, and histopathological images and cultured colonies confirm successful brain infection. Then, whole-brain tissue is dissected for 10X Genomics single-cell sequencing, and we acquire 15 cell types. Transcriptional changes of inflammation processes are found in multiple cell types. Specifically, Stat1 and IRF1 are shown to mediate inflammation in macrophages and microglia. For neurons, decreased oxidative phosphorylation activity in neurons is observed, which corresponds to TBM clinical symptoms of neurodegeneration. Finally, ependymal cells present prominent transcriptional changes, and decreased FERM domain containing 4A (Frmd4a) may contribute to TBM clinical symptoms of hydrocephalus and neurodegeneration. This study shows a single-cell transcriptome of M. bovis infection in mice and improves the understanding of brain infection and neurological complications in TBM.
Topics: Animals; Mice; Tuberculosis, Meningeal; BCG Vaccine; Brain; Inflammation; Single-Cell Analysis; Mycobacterium tuberculosis
PubMed: 36862557
DOI: 10.1016/j.celrep.2023.112177 -
Immunity Nov 2022Border-associated macrophages (BAMs) reside at the interface between the brain and the periphery, including the meninges and choroid plexus. In this issue of Immunity,...
Border-associated macrophages (BAMs) reside at the interface between the brain and the periphery, including the meninges and choroid plexus. In this issue of Immunity, two studies report the dynamics, diversity, and fate of murine BAMs during infection, assigning these cells a neuroprotective role.
Topics: Animals; Mice; Meninges; Macrophages; Choroid Plexus; Brain
PubMed: 36351369
DOI: 10.1016/j.immuni.2022.10.013 -
Cancer Treatment and Research... 2021No large-scale study evaluating the usefulness of tamoxifen after meningioma surgery has been undertaken.
BACKGROUND
No large-scale study evaluating the usefulness of tamoxifen after meningioma surgery has been undertaken.
METHODS
We processed the French Système National des Données de Santé (SNDS) database using an algorithm combining the type of surgical procedure and the International Classification of Diseases to retrieve cases of meningiomas operated between 2007 and 2017. Survival analyses were performed using a matched cohort study.
RESULTS
251 patients treated by tamoxifen were extracted from a nationwide population-based cohort of 28 924 patients operated on for a meningioma over a 10-year period. 94% were female and median age at meningioma first surgery was 57 years IQR[47-67]. Tamoxifen treatment median duration was 1.4 years IQR[0.4-3.2]. Tamoxifen treatment median cumulative given dose was 11.4 gs, IQR[3.6-24.9]. There was a strong positive correlation between treatment duration and cumulative dose (τ=0.81, p<0.001). 6% of the patient had to be reoperated for a meningioma recurrence and 26.3% had radiotherapy. OS rates at 5 and 10 years were: 92.3%, CI[90.3-94.3] and 81.3%, CI[75.2-88] respectively. These 251 patients were matched by gender, age at surgery and grade with the same number of subjects within the nationwide cohort. Nor overall (HR=1.46, CI[0.86- 2.49], p=0.163) or progression-free survival (HR=1.2, CI[0.89- 1.62], p=0.239) were significantly improved by the tamoxifen treatment.
CONCLUSION
Using this unique database, in the setting of breast cancer, we could not conclude on a favourable effect of tamoxifen to prevent recurrence after meningioma surgery or to increase meningioma-related survival even in case of prolonged treatment duration or high cumulative given dose.
Topics: Aged; Chemoradiotherapy, Adjuvant; Chemotherapy, Adjuvant; Databases, Factual; Dose-Response Relationship, Drug; Female; France; Humans; Male; Meningeal Neoplasms; Meninges; Meningioma; Middle Aged; Neoplasm Recurrence, Local; Progression-Free Survival; Retrospective Studies; Survival Analysis; Tamoxifen; Time Factors
PubMed: 33647870
DOI: 10.1016/j.ctarc.2021.100343 -
AJNR. American Journal of Neuroradiology Feb 2022The arachnoid membranes are projections of connective tissue in the subarachnoid space that connect the arachnoid mater to the pia mater. These are underappreciated and... (Review)
Review
The arachnoid membranes are projections of connective tissue in the subarachnoid space that connect the arachnoid mater to the pia mater. These are underappreciated and largely unrecognized by most neuroradiologists despite being found to be increasingly important in the pathogenesis, imaging, and treatment of communicating hydrocephalus. This review aims to provide neuroradiologists with an overview of the history, embryology, histology, anatomy, and normal imaging appearance of these membranes, as well as some examples of their clinical importance.
Topics: Arachnoid; Consciousness; Humans; Pia Mater; Radiology; Subarachnoid Space
PubMed: 34711549
DOI: 10.3174/ajnr.A7309 -
Molecular Psychiatry Apr 2021The potential existence and roles of the meningeal lymphatic system in normal and pathological brain function have been a long-standing enigma. Recent evidence suggests... (Review)
Review
The potential existence and roles of the meningeal lymphatic system in normal and pathological brain function have been a long-standing enigma. Recent evidence suggests that meningeal lymphatic vessels are present in both the mouse and human brain; in mice, they seem to play a role in clearing toxic amyloid-beta peptides, which have been connected with Alzheimer disease (AD). Here, we review the evidence linking the meningeal lymphatic system with human AD. Novel findings suggest that the recently described meningeal lymphatic vessels could be linked to, and possibly drain, the efferent paravascular glial lymphatic (glymphatic) system carrying cerebrospinal fluid, after solute and immune cell exchange with brain interstitial fluid. In so doing, the glymphatic system could contribute to the export of toxic solutes and immune cells from the brain (an exported fluid we wish to describe as glymph, similarly to lymph) to the meningeal lymphatic system; the latter, by being connected with downstream anatomic regions, carries the glymph to the conventional cervical lymphatic vessels and nodes. Thus, abnormal function in the meningeal lymphatic system could, in theory, lead to the accumulation, in the brain, of amyloid-beta, cellular debris, and inflammatory mediators, as well as immune cells, resulting in damage of the brain parenchyma and, in turn, cognitive and other neurologic dysfunctions. In addition, we provide novel insights into APOE4-the leading genetic risk factor for AD-and its relation to the meningeal lymphatic system. In this regard, we have reanalyzed previously published RNA-Seq data to show that induced pluripotent stem cells (iPSCs) carrying the APOE4 allele (either as APOE4 knock-in or stemming from APOE4 patients) express lower levels of (a) genes associated with lymphatic markers, and (b) genes for which well-characterized missense mutations have been linked to peripheral lymphedema. Taking into account this evidence, we propose a new conceptual framework, according to which APOE4 could play a novel role in the premature shrinkage of meningeal lymphatic vessels (meningeal lymphosclerosis), leading to abnormal meningeal lymphatic functions (meningeal lymphedema), and, in turn, reduction in the clearance of amyloid-beta and other macromolecules and inflammatory mediators, as well as immune cells, from the brain, exacerbation of AD manifestations, and progression of the disease. Altogether, these findings and their potential interpretations may herald novel diagnostic tools and therapeutic approaches in patients with AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoprotein E3; Apolipoprotein E4; Brain; Humans; Lymphatic System; Lymphatic Vessels; Meninges; Mice
PubMed: 32355332
DOI: 10.1038/s41380-020-0731-7 -
STAR Protocols Mar 2023The highly vascularized meninges protect the surface of the central nervous system and contain a dense network of immune cells controlling neuroinfection and...
The highly vascularized meninges protect the surface of the central nervous system and contain a dense network of immune cells controlling neuroinfection and neuroinflammation. Here, we present techniques for the immunological and virological assessment of mouse dural meninges. We describe steps for immunophenotyping including meninges extraction and digestion, immunostaining, and flow cytometry. We then describe viral assessment upon lymphocytic choriomeningitis virus infection including steps for fixation of the meninges in the skull, whole-mount immunohistochemistry, and confocal imaging. For complete details on the use and execution of this protocol, please refer to Rebejac et al. (2022)..
Topics: Animals; Mice; Flow Cytometry; Immunohistochemistry; Central Nervous System; Meninges; Head
PubMed: 36853673
DOI: 10.1016/j.xpro.2023.102119 -
Pain Sep 2021The genesis of the headache phase in migraine with aura is thought to be mediated by cortical spreading depression (CSD) and the subsequent activation and sensitization...
The genesis of the headache phase in migraine with aura is thought to be mediated by cortical spreading depression (CSD) and the subsequent activation and sensitization of primary afferent neurons that innervate the intracranial meninges and their related large vessels. Yet, the exact mechanisms underlying this peripheral meningeal nociceptive response remain poorly understood. We investigated the relative contribution of cortical astrocytes to CSD-evoked meningeal nociception using extracellular single-unit recording of meningeal afferent activity and 2-photon imaging of cortical astrocyte calcium activity, in combination with 2 pharmacological approaches to inhibit astrocytic function. We found that fluoroacetate and l-α-aminoadipate, which inhibit astrocytes through distinct mechanisms, suppressed CSD-evoked afferent mechanical sensitization, but did not affect afferent activation. Pharmacological inhibition of astrocytic function, which ameliorated meningeal afferents' sensitization, reduced basal astrocyte calcium activity but had a minimal effect on the astrocytic calcium wave during CSD. We propose that calcium-independent signaling in cortical astrocytes plays an important role in driving the sensitization of meningeal afferents and the ensuing intracranial mechanical hypersensitivity in migraine with aura.
Topics: Animals; Astrocytes; Cortical Spreading Depression; Meninges; Migraine Disorders; Nociceptors; Rats; Rats, Sprague-Dawley
PubMed: 34448752
DOI: 10.1097/j.pain.0000000000002229 -
Nature Communications Mar 2022The epidemiology of infectious causes of meningitis in sub-Saharan Africa is not well understood, and a common cause of meningitis in this region, Mycobacterium...
The epidemiology of infectious causes of meningitis in sub-Saharan Africa is not well understood, and a common cause of meningitis in this region, Mycobacterium tuberculosis (TB), is notoriously hard to diagnose. Here we show that integrating cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) with a host gene expression-based machine learning classifier (MLC) enhances diagnostic accuracy for TB meningitis (TBM) and its mimics. 368 HIV-infected Ugandan adults with subacute meningitis were prospectively enrolled. Total RNA and DNA CSF mNGS libraries were sequenced to identify meningitis pathogens. In parallel, a CSF host transcriptomic MLC to distinguish between TBM and other infections was trained and then evaluated in a blinded fashion on an independent dataset. mNGS identifies an array of infectious TBM mimics (and co-infections), including emerging, treatable, and vaccine-preventable pathogens including Wesselsbron virus, Toxoplasma gondii, Streptococcus pneumoniae, Nocardia brasiliensis, measles virus and cytomegalovirus. By leveraging the specificity of mNGS and the sensitivity of an MLC created from CSF host transcriptomes, the combined assay has high sensitivity (88.9%) and specificity (86.7%) for the detection of TBM and its many mimics. Furthermore, we achieve comparable combined assay performance at sequencing depths more amenable to performing diagnostic mNGS in low resource settings.
Topics: Central Nervous System; Humans; Meningitis; Metagenomics; Mycobacterium tuberculosis; Tuberculosis, Meningeal
PubMed: 35354815
DOI: 10.1038/s41467-022-29353-x -
Neurobiology of Disease Dec 2023Cerebral small vessel disease (CSVD) causes 20%-25% of stroke and contributes to 45% of dementia cases worldwide. However, since its early symptoms are inconclusive in... (Review)
Review
Cerebral small vessel disease (CSVD) causes 20%-25% of stroke and contributes to 45% of dementia cases worldwide. However, since its early symptoms are inconclusive in addition to the complexity of the pathological basis, there is a rather limited effective therapies and interventions. Recently, accumulating evidence suggested that various brain-waste-clearance dysfunctions are closely related to the pathogenesis and prognosis of CSVD, and after a comprehensive and systematic review we classified them into two broad categories: trans-barrier transport and lymphatic drainage. The former includes blood brain barrier and blood-cerebrospinal fluid barrier, and the latter, glymphatic-meningeal lymphatic system and intramural periarterial drainage pathway. We summarized the concepts and potential mechanisms of these clearance systems, proposing a relatively complete framework for elucidating their interactions with CSVD. In addition, we also discussed recent advances in therapeutic strategies targeting clearance dysfunction, which may be an important area for future CSVD research.
Topics: Humans; Blood-Brain Barrier; Glymphatic System; Stroke; Cerebral Small Vessel Diseases; Meninges; Brain
PubMed: 37951367
DOI: 10.1016/j.nbd.2023.106347 -
Journal of Clinical Microbiology Oct 2023Rapid identification of the causative pathogens of central nervous system infections is essential for providing appropriate management and improving patient outcomes....
Rapid identification of the causative pathogens of central nervous system infections is essential for providing appropriate management and improving patient outcomes. The performance of QIAstat-Dx Meningitis/Encephalitis (ME) Panel-a multiplex PCR testing platform-in detecting pathogens implicated in meningitis and/or encephalitis was evaluated using BioFire FilmArray ME Panel as a comparator method. This multicenter study analyzed 585 retrospective residual cerebrospinal fluid specimens and 367 contrived specimens. The QIAstat-Dx ME Panel showed positive percent agreement (PPA) values of 100% for , , K1, , and / on clinical samples compared to the BioFire FilmArray ME Panel. The PPA values observed for and were 80% and 88.24%, respectively. Negative percent agreement (NPA) values were >99.0% for each of the six bacterial targets and one fungal target tested with clinical samples. One viral target, herpes simplex virus 1, exhibited a PPA value of 100.0%, while the remaining viral targets-human parechovirus, herpes simplex virus 2, human herpes virus 6, and varicella zoster virus-were >90.0%, with the exception of enterovirus, which had a PPA value of 77.8%. The QIAstat-Dx ME Panel detected five true-positive and four true-negative cases compared to BioFire FilmArray ME Panel. The NPA values for all viral pathogens were >99.0%. Overall, the QIAstat-Dx ME Panel showed comparable performance to the BioFire FilmArray ME Panel as a rapid diagnostic tool for community-acquired meningitis and encephalitis.
Topics: Humans; Multiplex Polymerase Chain Reaction; Retrospective Studies; Meningitis; Encephalitis; Meningoencephalitis
PubMed: 37702495
DOI: 10.1128/jcm.00426-23