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Biomolecules May 2022There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main... (Review)
Review
There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main contributor to VCI. Several potential physiopathologic mechanisms have been proven to be involved in the process of CSVD, such as blood-brain barrier damage, small vessels stiffening, venous collagenosis, cerebral blood flow reduction, white matter rarefaction, chronic ischaemia, neuroinflammation, myelin damage, and subsequent neurodegeneration. However, there still is a limited overall understanding of the sequence and the relative importance of these mechanisms. The glymphatic system (GS) and meningeal lymphatic vessels (mLVs) are the analogs of the lymphatic system in the central nervous system (CNS). As such, these systems play critical roles in regulating cerebrospinal fluid (CSF) and interstitial fluid (ISF) transport, waste clearance, and, potentially, neuroinflammation. Accumulating evidence has suggested that the glymphatic and meningeal lymphatic vessels played vital roles in animal models of CSVD and patients with CSVD. Given the complexity of CSVD, it was significant to understand the underlying interaction between glymphatic and meningeal lymphatic transport with CSVD. Here, we provide a novel framework based on new advances in main four aspects, including vascular risk factors, potential mechanisms, clinical subtypes, and cognition, which aims to explain how the glymphatic system and meningeal lymphatic vessels contribute to the progression of CSVD and proposes a comprehensive insight into the novel therapeutic strategy of CSVD.
Topics: Animals; Brain; Central Nervous System; Cerebral Small Vessel Diseases; Glymphatic System; Humans; Lymphatic System; Meninges
PubMed: 35740873
DOI: 10.3390/biom12060748 -
Molecular Neurodegeneration Aug 2023Alzheimer's disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in... (Review)
Review
Alzheimer's disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in the brain. These phenomena are accompanied by exacerbated inflammation and marked neuronal loss, which altogether contribute to accelerated cognitive decline. The multifactorial nature of AD, allied to our still limited knowledge of its etiology and pathophysiology, have lessened our capacity to develop effective treatments for AD patients. Over the last few decades, genome wide association studies and biomarker development, alongside mechanistic experiments involving animal models, have identified different immune components that play key roles in the modulation of brain pathology in AD, affecting its progression and severity. As we will relay in this review, much of the recent efforts have been directed to better understanding the role of brain innate immunity, and particularly of microglia. However, and despite the lack of diversity within brain resident immune cells, the brain border tissues, especially the meninges, harbour a considerable number of different types and subtypes of adaptive and innate immune cells. Alongside microglia, which have taken the centre stage as important players in AD research, there is new and exciting evidence pointing to adaptive immune cells, namely T and B cells found in the brain and its meninges, as important modulators of neuroinflammation and neuronal (dys)function in AD. Importantly, a genuine and functional lymphatic vascular network is present around the brain in the outermost meningeal layer, the dura. The meningeal lymphatics are directly connected to the peripheral lymphatic system in different mammalian species, including humans, and play a crucial role in preserving a "healthy" immune surveillance of the CNS, by shaping immune responses, not only locally at the meninges, but also at the level of the brain tissue. In this review, we will provide a comprehensive view on our current knowledge about the meningeal lymphatic vasculature, emphasizing its described roles in modulating CNS fluid and macromolecule drainage, meningeal and brain immunity, as well as glial and neuronal function in aging and in AD.
Topics: Animals; Humans; Alzheimer Disease; Amyloid beta-Peptides; Genome-Wide Association Study; Meninges; Lymphatic System; Brain; Mammals
PubMed: 37580702
DOI: 10.1186/s13024-023-00645-0 -
Nature Nov 2020The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain...
The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain and spinal cord-contain a diverse population of immune cells. So far, studies have focused on macrophages and T cells, but have not included a detailed analysis of meningeal humoral immunity. Here we show that, during homeostasis, the mouse and human meninges contain IgA-secreting plasma cells. These cells are positioned adjacent to dural venous sinuses: regions of slow blood flow with fenestrations that can potentially permit blood-borne pathogens to access the brain. Peri-sinus IgA plasma cells increased with age and following a breach of the intestinal barrier. Conversely, they were scarce in germ-free mice, but their presence was restored by gut re-colonization. B cell receptor sequencing confirmed that meningeal IgA cells originated in the intestine. Specific depletion of meningeal plasma cells or IgA deficiency resulted in reduced fungal entrapment in the peri-sinus region and increased spread into the brain following intravenous challenge, showing that meningeal IgA is essential for defending the central nervous system at this vulnerable venous barrier surface.
Topics: Aged; Aging; Animals; Blood-Brain Barrier; Cranial Sinuses; Female; Fungi; Gastrointestinal Microbiome; Germ-Free Life; Humans; Immunoglobulin A, Secretory; Intestines; Male; Meninges; Mice; Mice, Inbred C57BL; Plasma Cells
PubMed: 33149302
DOI: 10.1038/s41586-020-2886-4 -
Magnetic Resonance in Medical Sciences... Mar 2022The central nervous system (CNS) was previously thought to be the only organ system lacking lymphatic vessels to remove waste products from the interstitial space.... (Review)
Review
The central nervous system (CNS) was previously thought to be the only organ system lacking lymphatic vessels to remove waste products from the interstitial space. Recently, based on the results from animal experiments, the glymphatic system was hypothesized. In this hypothesis, cerebrospinal fluid (CSF) enters the periarterial spaces, enters the interstitial space of the brain parenchyma via aquaporin-4 (AQP4) channels in the astrocyte end feet, and then exits through the perivenous space, thereby clearing waste products. From the perivenous space, the interstitial fluid drains into the subarachnoid space and meningeal lymphatics of the parasagittal dura. It has been reported that the glymphatic system is particularly active during sleep. Impairment of glymphatic system function might be a cause of various neurodegenerative diseases such as Alzheimer's disease, normal pressure hydrocephalus, glaucoma, and others. Meningeal lymphatics regulate immunity in the CNS. Many researchers have attempted to visualize the function and structure of the glymphatic system and meningeal lymphatics in vivo using MR imaging. In this review, we aim to summarize these in vivo MR imaging studies and discuss the significance, current limitations, and future directions. We also discuss the significance of the perivenous cyst formation along the superior sagittal sinus, which is recently discovered in the downstream of the glymphatic system.
Topics: Animals; Brain; Central Nervous System; Glymphatic System; Magnetic Resonance Imaging; Meninges
PubMed: 33250472
DOI: 10.2463/mrms.rev.2020-0122 -
Developmental Cell Jul 2020The meninges are a multilayered structure composed of fibroblasts, blood and lymphatic vessels, and immune cells. Meningeal fibroblasts secrete a variety of factors that...
The meninges are a multilayered structure composed of fibroblasts, blood and lymphatic vessels, and immune cells. Meningeal fibroblasts secrete a variety of factors that control CNS development, yet strikingly little is known about their heterogeneity or development. Using single-cell sequencing, we report distinct transcriptional signatures for fibroblasts in the embryonic dura, arachnoid, and pia. We define new markers for meningeal layers and show conservation in human meninges. We find that embryonic meningeal fibroblasts are transcriptionally distinct between brain regions and identify a regionally localized pial subpopulation marked by the expression of μ-crystallin. Developmental analysis reveals a progressive, ventral-to-dorsal maturation of telencephalic meninges. Our studies have generated an unparalleled view of meningeal fibroblasts, providing molecular profiles of embryonic meningeal fibroblasts by layer and yielding insights into the mechanisms of meninges development and function.
Topics: Animals; Brain; Crystallins; Fibroblasts; Humans; Meninges; Mice; Mice, Inbred C57BL; RNA-Seq; Single-Cell Analysis; Transcriptome
PubMed: 32634398
DOI: 10.1016/j.devcel.2020.06.009 -
Nature Neuroscience Feb 2019Analysis of entire transparent rodent bodies after clearing could provide holistic biological information in health and disease, but reliable imaging and quantification...
Analysis of entire transparent rodent bodies after clearing could provide holistic biological information in health and disease, but reliable imaging and quantification of fluorescent protein signals deep inside the tissues has remained a challenge. Here, we developed vDISCO, a pressure-driven, nanobody-based whole-body immunolabeling technology to enhance the signal of fluorescent proteins by up to two orders of magnitude. This allowed us to image and quantify subcellular details through bones, skin and highly autofluorescent tissues of intact transparent mice. For the first time, we visualized whole-body neuronal projections in adult mice. We assessed CNS trauma effects in the whole body and found degeneration of peripheral nerve terminals in the torso. Furthermore, vDISCO revealed short vascular connections between skull marrow and brain meninges, which were filled with immune cells upon stroke. Thus, our new approach enables unbiased comprehensive studies of the interactions between the nervous system and the rest of the body.
Topics: Animals; Meninges; Mice; Mice, Transgenic; Neurons; Skull; Whole Body Imaging
PubMed: 30598527
DOI: 10.1038/s41593-018-0301-3 -
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 -
Annual Review of Neuroscience Jul 2023Migraine is a complex neurovascular pain disorder linked to the meninges, a border tissue innervated by neuropeptide-containing primary afferent fibers chiefly from the... (Review)
Review
Migraine is a complex neurovascular pain disorder linked to the meninges, a border tissue innervated by neuropeptide-containing primary afferent fibers chiefly from the trigeminal nerve. Electrical or mechanical stimulation of this nerve surrounding large blood vessels evokes headache patterns as in migraine, and the brain, blood, and meninges are likely sources of headache triggers. Cerebrospinal fluid may play a significant role in migraine by transferring signals released from the brain to overlying pain-sensitive meningeal tissues, including dura mater. Interactions between trigeminal afferents, neuropeptides, and adjacent meningeal cells and tissues cause neurogenic inflammation, a critical target for current prophylactic and abortive migraine therapies. Here we review the importance of the cranial meninges to migraine headaches, explore the properties of trigeminal meningeal afferents, and briefly review emerging concepts, such as meningeal neuroimmune interactions, that may one day prove therapeutically relevant.
Topics: Humans; Migraine Disorders; Meninges; Dura Mater; Headache; Brain
PubMed: 36913712
DOI: 10.1146/annurev-neuro-080422-105509 -
The Oncologist Sep 2008Neoplastic meningitis (NM) is a common problem in neuro-oncology, occurring in approximately 5% of all patients with cancer. (Review)
Review
BACKGROUND
Neoplastic meningitis (NM) is a common problem in neuro-oncology, occurring in approximately 5% of all patients with cancer.
METHODS
Notwithstanding frequent focal signs and symptoms, NM is a disease affecting the entire neuraxis, and therefore staging and treatment need encompass all cerebrospinal fluid (CSF) compartments.
RESULTS
Central nervous system staging of NM includes contrast-enhanced cranial computerized tomography or magnetic resonance imaging (MR-Gd), contrast-enhanced spine magnetic resonance imaging or computerized tomographic myelography and radionuclide CSF flow study. Treatment of NM incorporates involved-field radiotherapy of bulky or symptomatic disease sites and intra-CSF drug therapy. The inclusion of concomitant systemic therapy may benefit patients with NM and may obviate the need for intra-CSF chemotherapy. At present, intra-CSF drug therapy is confined to three chemotherapeutic agents (i.e., methotrexate, cytosine, arabinoside, and thio-TEPA) administered by a variety of schedules either by intralumbar or intraventricular drug delivery.
CONCLUSIONS
Although treatment of NM is palliative with an expected median patient survival of 2 to 6 months, it often affords stabilization and protection from further neurologic deterioration in patients with NM.
Topics: Humans; Meningeal Carcinomatosis; Meningeal Neoplasms; Meningitis
PubMed: 18776058
DOI: 10.1634/theoncologist.2008-0138 -
Internal Medicine (Tokyo, Japan) 2006Although meningism manifesting acute headache has been observed to be associated with common viral and bacterial infections, its definition and pathogenesis have not... (Comparative Study)
Comparative Study
OBJECTIVE
Although meningism manifesting acute headache has been observed to be associated with common viral and bacterial infections, its definition and pathogenesis have not been clarified. Clinical findings and cerebrospinal fluid (CSF) cytokines in adult patients with meningism were investigated and compared with those in viral meningitis.
PATIENTS AND METHODS
Among the adult inpatients in our hospital from 1997 to 2004, 5 with meningism and 17 with viral meningitis were identified according to the criteria described in this study, and their clinical data were analyzed. In the CSF samples of the 5 patients with meningism and the 17 with viral meningitis, the concentrations of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, and IL-10 were determined using a cytometric bead array.
RESULTS
The five patients with meningism all showed fever and meningeal signs such as severe headache and nuchal stiffness without CSF pleocytosis (<5 cells/mm3). Four patients were associated with herpetic Kaposi's eczema, herpes simplex, or herpes zoster, and all five patients had favorable outcomes. The levels of all CSF cytokines in patients with meningism were below normal values, whereas IFN-gamma and IL-6 in patients with viral meningitis were moderately elevated.
CONCLUSION
The normal cytokine levels in meningism may possibly reflect the lack of direct viral infection and may be helpful in differentiating both meningism and viral meningitis at an early stage.
Topics: Adult; Aged; Cytokines; Female; Hospitalization; Humans; Male; Meningism; Meningitis, Viral; Middle Aged
PubMed: 17139119
DOI: 10.2169/internalmedicine.45.1769