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Nature Communications Aug 2022Major depressive disorder is one of the most common mental health conditions. Meningeal lymphatics are essential for drainage of molecules in the cerebrospinal fluid to...
Major depressive disorder is one of the most common mental health conditions. Meningeal lymphatics are essential for drainage of molecules in the cerebrospinal fluid to the peripheral immune system. Their potential role in depression-like behaviour has not been investigated. Here, we show in mice, sub-chronic variable stress as a model of depression-like behaviour impairs meningeal lymphatics in females but not in males. Manipulations of meningeal lymphatics regulate the sex difference in the susceptibility to stress-induced depression- and anxiety-like behaviors in mice, as well as alterations of the medial prefrontal cortex and the ventral tegmental area, brain regions critical for emotional regulation. Together, our findings suggest meningeal lymphatic impairment contributes to susceptibility to stress in mice, and that restoration of the meningeal lymphatics might have potential for modulation of depression-like behaviour.
Topics: Animals; Depressive Disorder, Major; Female; Lymphatic System; Lymphatic Vessels; Male; Meninges; Mice; Sex Characteristics; Stress, Psychological
PubMed: 35974004
DOI: 10.1038/s41467-022-32556-x -
Neuron Nov 2022In an interview with Neuron, Jony Kipnis discusses his formative academic years and subsequent discoveries in meningeal lymphatics. He is enthusiastic about the prospect...
In an interview with Neuron, Jony Kipnis discusses his formative academic years and subsequent discoveries in meningeal lymphatics. He is enthusiastic about the prospect of therapeutic developments in neuroimmunology arising from focusing on the brain's borders.
Topics: Humans; Male; Lymphatic System; Meninges
PubMed: 36327892
DOI: 10.1016/j.neuron.2022.10.010 -
The Journal of Experimental Medicine Jul 2023The meningeal lymphatic network enables the drainage of cerebrospinal fluid (CSF) and facilitates the removal of central nervous system (CNS) waste. During aging and in...
The meningeal lymphatic network enables the drainage of cerebrospinal fluid (CSF) and facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer's disease, impaired meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins in the CNS. Reversing this age-related dysfunction represents a promising strategy to augment CNS waste clearance; however, the mechanisms underlying this decline remain elusive. Here, we demonstrate that age-related alterations in meningeal immunity underlie this lymphatic impairment. Single-cell RNA sequencing of meningeal lymphatic endothelial cells from aged mice revealed their response to IFNγ, which was increased in the aged meninges due to T cell accumulation. Chronic elevation of meningeal IFNγ in young mice via AAV-mediated overexpression attenuated CSF drainage-comparable to the deficits observed in aged mice. Therapeutically, IFNγ neutralization alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable approach to normalize CSF drainage and alleviate the neurological deficits associated with impaired waste removal.
Topics: Mice; Animals; Endothelial Cells; Central Nervous System; Meninges; Lymphatic Vessels; Alzheimer Disease; Lymphatic System; Brain
PubMed: 37027179
DOI: 10.1084/jem.20221929 -
Genome Medicine May 2022Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role....
BACKGROUND
Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples.
METHODS
Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers.
RESULTS
In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples.
CONCLUSIONS
Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura.
Topics: Animals; Endothelial Cells; Humans; Immunity; Meningeal Neoplasms; Meninges; Meningioma; Mice; Tumor Microenvironment
PubMed: 35534852
DOI: 10.1186/s13073-022-01051-9 -
Neurobiology of Disease Feb 2023Recent human and animal model experimental studies revealed novel pathways for fluid movement, immune cell trafficking and metabolic waste clearance in CNS. These... (Review)
Review
Recent human and animal model experimental studies revealed novel pathways for fluid movement, immune cell trafficking and metabolic waste clearance in CNS. These studies raise the intriguing possibility that the newly discovered pathways, including the glymphatic system, lymphatic meningeal vessels and skull-brain communication channels, are impaired in aging and neurovascular and neurodegenerative diseases associated with dementia, including Alzheimer's disease (AD) and AD-related dementia. We provide an overview of the glymphatic and dural meningeal lymphatic systems, review current methods and approaches used to study glymphatic flow in humans and animals, and discuss current evidence and controversies related to its role in CNS flow homeostasis under physiological and pathophysiological conditions. Non-invasive imaging approaches are needed to fully understand the mechanisms and pathways driving fluid movement in CNS and their roles across lifespan including healthy aging and aging-related dementia.
Topics: Animals; Humans; Hydrodynamics; Brain; Meninges; Glymphatic System; Alzheimer Disease
PubMed: 36603747
DOI: 10.1016/j.nbd.2022.105986 -
PloS One 2023Tuberculosis (TB) which is caused by Mycobacterium tuberculosis poses a significant public health global treat. Tuberculosis meningitis (TBM) accounts for approximately... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Tuberculosis (TB) which is caused by Mycobacterium tuberculosis poses a significant public health global treat. Tuberculosis meningitis (TBM) accounts for approximately 1% of all active TB cases. The diagnosis of Tuberculosis meningitis is notably difficult due to its rapid onset, nonspecific symptoms, and the difficulty of detecting Mycobacterium tuberculosis in cerebrospinal fluid (CSF). In 2019, 78,200 adults died of TB meningitis. This study aimed to assess the microbiological diagnosis TB meningitis using CSF and estimated the risk of death from TBM.
METHODS
Relevant electronic databases and gray literature sources were searched for studies that reported presumed TBM patients. The quality of included studies was assessed using the Joanna Briggs Institute Critical Appraisal tools designed for prevalence studies. Data were summarized using Microsoft excel ver 16. The proportion of culture confirmed TBM, prevalence of drug resistance and risk of death were calculated using the random-effect model. Stata version 16.0 was used perform the statistical analysis. Moreover, subgroup analysis was conducted.
RESULTS
After systematic searching and quality assessment, 31 studies were included in the final analysis. Ninety percent of the included studies were retrospective studies in design. The overall pooled estimates of CSF culture positive TBM was 29.72% (95% CI; 21.42-38.02). The pooled prevalence of MDR-TB among culture positive TBM cases was 5.19% (95% CI; 3.12-7.25). While, the proportion of INH mono-resistance was 9.37% (95% CI; 7.03-11.71). The pooled estimate of case fatality rate among confirmed TBM cases was 20.42% (95%CI; 14.81-26.03). Based on sub group analysis, the pooled case fatality rate among HIV positive and HIV negative TBM individuals was 53.39% (95%CI; 40.55-66.24) and 21.65% (95%CI;4.27-39.03) respectively.
CONCLUSION
Definite diagnosis of TBM still remains global treat. Microbiological confirmation of TBM is not always achievable. Early microbiological confirmation of TBM has great importance to reduce mortality. There was high rate of MDR-TB among confirmed TBM patients. All TB meningitis isolates should be cultured and drug susceptibility tested using standard techniques.
Topics: Adult; Humans; Tuberculosis, Meningeal; Retrospective Studies; Sensitivity and Specificity; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 36795648
DOI: 10.1371/journal.pone.0279203 -
Cell Stem Cell Nov 2023The meninges lie in the interface between the skull and brain, harboring lymphatic vasculature and skull progenitor cells (SPCs). How the skull and brain communicate...
The meninges lie in the interface between the skull and brain, harboring lymphatic vasculature and skull progenitor cells (SPCs). How the skull and brain communicate remains largely unknown. We found that impaired meningeal lymphatics and brain perfusion drive neurocognitive defects in Twist1 mice, an animal model of craniosynostosis recapitulating human Saethre-Chotzen syndrome. Loss of SPCs leads to skull deformities and elevated intracranial pressure (ICP), whereas transplanting SPCs back into mutant mice mitigates lymphatic and brain defects through two mechanisms: (1) decreasing elevated ICP by skull correction and (2) promoting the growth and migration of lymphatic endothelial cells (LECs) via SPC-secreted vascular endothelial growth factor-C (VEGF-C). Treating Twist1 mice with VEGF-C promotes meningeal lymphatic growth and rescues defects in ICP, brain perfusion, and neurocognitive functions. Thus, the skull functionally integrates with the brain via meningeal lymphatics, which is impaired in craniosynostosis and can be restored by SPC-driven lymphatic activation via VEGF-C.
Topics: Mice; Humans; Animals; Vascular Endothelial Growth Factor C; Endothelial Cells; Skull; Meninges; Craniosynostoses; Stem Cells
PubMed: 37863055
DOI: 10.1016/j.stem.2023.09.012 -
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 -
European Neurology 2021More than a century separates the description of "dropsy of the ventricles of the brain" by Scottish physicians and Robert Koch's identification of the causal agent of... (Review)
Review
More than a century separates the description of "dropsy of the ventricles of the brain" by Scottish physicians and Robert Koch's identification of the causal agent of tuberculous meningitis in 1882. This article reviews the writings in Scotland and France that marked the history of the identification of this infectious entity. From John Paisley in 1734 to Robert Whytt in 1738, from Marcellin Chardel in 1799 and L.P. Collinet in 1802 to Isidore Bricheteau in 1814 and Jean-Louis Brachet in 1818, and then Victor Le Diberder in 1837 and Isidore Valleix in 1838, unknown and forgotten physicians outnumber the famous masters in bringing about the progress and knowledge that enabled this frequent and consistently fatal disease in the 19th century to be accurately diagnosed and in most cases cured in the 20th century.
Topics: France; History, 18th Century; History, 19th Century; History, 20th Century; Humans; Physicians; Tuberculosis, Meningeal
PubMed: 33326957
DOI: 10.1159/000512468 -
Journal of Neuroinflammation May 2023The meninges, membranes surrounding the central nervous system (CNS) boundary, harbor a diverse array of immunocompetent immune cells, and therefore, serve as an... (Review)
Review
The meninges, membranes surrounding the central nervous system (CNS) boundary, harbor a diverse array of immunocompetent immune cells, and therefore, serve as an immunologically active site. Meningeal immunity has emerged as a key factor in modulating proper brain function and social behavior, performing constant immune surveillance of the CNS, and participating in several neurological diseases. However, it remains to be determined how meningeal immunity contributes to CNS physiology and pathophysiology. With the advances in single-cell omics, new approaches, such as single-cell technologies, unveiled the details of cellular and molecular mechanisms underlying meningeal immunity in CNS homeostasis and dysfunction. These new findings contradict some previous dogmas and shed new light on new possible therapeutic targets. In this review, we focus on the complicated multi-components, powerful meningeal immunosurveillance capability, and its crucial involvement in physiological and neuropathological conditions, as recently revealed by single-cell technologies.
Topics: Humans; Meninges; Central Nervous System; Nervous System Diseases
PubMed: 37231449
DOI: 10.1186/s12974-023-02803-z