Meningeal Vessels Research Articles

Abstract WMP110: Vascular Endothelial Growth Factor C Confers Neuroprotection And Ameliorates Ischemic Stroke Outcomes

Meningeal lymphatic vessels (MLVs) promote clearance and immune surveillance of central nervous system (CNS) 1 tissue. Vascular Endothelium Growth Factor-C (VEGF-C) regulates meningeal lymphatic growth and has shown therapeutic potential for neurological disorders such as cognitive aging 2 and brain tumors 3 , while stroke outcome is worsened by impaired MLV growth 4 . We hypothesized that VEGF-C delivery into the cerebrospinal fluid (CSF) might benefit stroke injury repair and investigated the effects of VEGF-C overexpression on brain fluid drainage, brain gene expression, and stroke outcome in adult mice. Adult male C57BL/6J mice received VEGF-C-expressing adeno-associated virus (AAV) or control AAV into CSF ( n = 10 per condition). Four weeks after AAV delivery, we used contrast-enhanced magnetic resonance imaging (MRI) for real-time tracking of a CSF-injected gadolinium-based solute tracer and quantifying CSF drainage. VEGF-C pretreatment did not alter glymphatic drainage and CSF efflux through the cribriform plate but increased deep cervical lymph nodes volume and drainage. Single nucleus RNA sequencing of forebrain cells isolated from AAV-VEGF-C or -control pretreated mice ( n = 5 per condition) revealed that VEGF-C upregulated the Brain-derived Neurotrophic Factor (BDNF) signaling pathway in brain interneurons. Finally, in a mouse model of ischemic stroke induced by 60 min of transient middle cerebral artery occlusion (tMCAO), AAV-VEGF-C pretreatment reduced lesion volume measured by MRI, improved motor performances evaluated using Neuroscore (at days 3 and 7 post-stroke) and Hanging wire test (at day 3 post-stroke) and increased brain expression of BDNF and NGF transcripts on day 7 post-stroke. Intra-CSF AAV-VEGF-C delivery before stroke can thus promote CNS-derived fluid drainage, induce neuroprotection, and protect against ischemic damage.

Development and application of a novel cervical lymph collection method to assess lymphatic transport in rats.

Background: Fluids, solutes and immune cells have been demonstrated to drain from the brain and surrounding structures to the cervical lymph vessels and nodes in the neck via meningeal lymphatics, nasal lymphatics and/or lymphatic vessels associated with cranial nerves. A method to cannulate the efferent cervical lymph duct for continuous cervical lymph fluid collection in rodents has not been described previously and would assist in evaluating the transport of molecules and immune cells from the head and brain via the lymphatics, as well as changes in lymphatic transport and lymph composition with different physiological challenges or diseases. Aim: To develop a novel method to cannulate and continuously collect lymph fluid from the cervical lymph duct in rats and to analyze the protein, lipid and immune cell composition of the collected cervical lymph fluid. Methods: Male Sprague-Dawley rats were cannulated at the carotid artery with or without cannulation or ligation at the cervical lymph duct. Samples of blood, whole lymph and isolated lipoprotein fractions of lymph were collected and analyzed for lipid and protein composition using commercial kits. Whole lymph samples were centrifuged and isolated pellets were stained and processed for flow cytometry analysis of CD3+, CD4+, CD8a+, CD45R+ (B220) and viable cell populations. Results: Flow rate, phospholipid, triglyceride, cholesterol ester, free cholesterol and protein concentrations in cervical lymph were 0.094 ± 0.014mL/h, 0.34 ± 0.10, 0.30 ± 0.04, 0.07 ± 0.02, 0.02 ± 0.01 and 16.78 ± 2.06mg/mL, respectively. Protein was mostly contained within the non-lipoprotein fraction but all lipoprotein types were also present. Flow cytometry analysis of cervical lymph showed that 67.1 ± 7.4% of cells were CD3+/CD4+ T lymphocytes, 5.8 ± 1.6% of cells were CD3+/CD8+ T lymphocytes, and 10.8 ± 4.6% of cells were CD3-/CD45R+ B lymphocytes. The remaining 16.3 ± 4.6% cells were CD3-/CD45- and identified as non-lymphocytes. Conclusion: Our novel cervical lymph cannulation method enables quantitative analysis of the lymphatic transport of immune cells and molecules in the cervical lymph of rats for the first time. This valuable tool will enable more detailed quantitative analysis of changes to cervical lymph composition and transport in health and disease, and could be a valuable resource for discovery of biomarkers or therapeutic targets in future studies.

Clinical and pathological characterization of Central Nervous System cryptococcosis in an experimental mouse model of stereotaxic intracerebral infection

Infection of the Central Nervous System (CNS) by the encapsulated fungus Cryptococcus neoformans can lead to high mortality meningitis, most commonly in immunocompromised patients. While the mechanisms by which the fungus crosses the blood-brain barrier to initiate infection in the CNS are well recognized, there are still substantial unanswered questions about the disease progression once the fungus is established in the brain. C. neoformans is characterized by a glucuronoxylomannan (GXM)-rich polysaccharide capsule which has been implicated in immune evasion, but its role during the host CNS infection needs further elucidation. Therefore, the present study aims to examine these key questions about the mechanisms underlying cryptococcal meningitis progression and the impact of fungal GXM release by using an intracerebral rodent infection model via stereotaxic surgery. After developing brain infection, we analyzed distinct brain regions and found that while fungal load and brain weight were comparable one-week post-infection, there were region-specific histopathological (with and without brain parenchyma involvement) and disease manifestations. Moreover, we also observed a region-specific correlation between GXM accumulation and glial cell recruitment. Furthermore, mortality was associated with the presence of subarachnoid hemorrhaging and GXM deposition in the meningeal blood vessels and meninges in all regions infected. Our results show that using the present infection model can facilitate clinical and neuropathological observations during the progression of neurocryptococcosis. Importantly, this mouse model can be used to further investigate disease progression as it develops in humans.

Dobutamine promotes the clearance of erythrocytes from the brain to cervical lymph nodes after subarachnoid hemorrhage in mice.

Background: Erythrocytes and their breakdown products in the subarachnoid space (SAS) are the main contributors to the pathogenesis of subarachnoid hemorrhage (SAH). Dobutamine is a potent β1-adrenoreceptor agonist that can increase cardiac output, thus improving blood perfusion and arterial pulsation in the brain. In this study, we investigated whether the administration of dobutamine promoted the clearance of red blood cells (RBCs) and their degraded products via meningeal lymphatic vessels (mLVs), thus alleviating neurological deficits in the early stage post-SAH. Materials and methods: Experimental SAH was induced by injecting autologous arterial blood into the prechiasmatic cistern in male C57BL/6 mice. Evans blue was injected into the cisterna magna, and dobutamine was administered by inserting a femoral venous catheter. RBCs in the deep cervical lymphatic nodes (dCLNs) were evaluated by hematoxylin-eosin staining, and the hemoglobin content in dCLNs was detected by Drabkin's reagent. The accumulation of RBCs in the dura mater was examined by immunofluorescence staining, neuronal death was evaluated by Nissl staining, and apoptotic cell death was evaluated by TUNEL staining. The Morris water maze test was used to examine the cognitive function of mice after SAH. Results: RBCs appeared in dCLNs as early as 3h post-SAH, and the hemoglobin in dCLNs peaked at 12h after SAH. Dobutamine significantly promoted cerebrospinal fluid (CSF) drainage from the SAS to dCLNs and obviously reduced the RBC residue in mLVs, leading to a decrease in neuronal death and an improvement in cognitive function after SAH. Conclusion: Dobutamine administration significantly promoted RBC drainage from cerebrospinal fluid in the SAS via mLVs into dCLNs, ultimately relieving neuronal death and improving cognitive function.

Streptococcus pneumoniae meningitis and the CNS barriers.

Streptococcus pneumoniae (SPN) is a globally significant cause of meningitis, the pathophysiology of which involves damage to the brain by both bacterial virulence factors and the host inflammatory response. In most cases of SPN meningitis bacteria translocate from the blood into the central nervous system (CNS). The principal site of SPN translocation into the CNS is not known, with possible portals of entry proposed to be the cerebral or meningeal blood vessels or the choroid plexus. All require SPN to bind to and translocate across the vascular endothelial barrier, and subsequently the basement membrane and perivascular structures, including an additional epithelial barrier in the case of the blood-CSF barrier. The presence of SPN in the CNS is highly inflammatory resulting in marked neutrophilic infiltration. The secretion of toxic inflammatory mediators by activated neutrophils within the CNS damages pathogen and host alike, including the non-replicative neurons which drives morbidity and mortality. As with the translocation of SPN, the recruitment of neutrophils into the CNS in SPN meningitis necessitates the translocation of neutrophils from the circulation across the vascular barrier, a process that is tightly regulated under basal conditions - a feature of the 'immune specialization' of the CNS. The brain barriers are therefore central to SPN meningitis, both through a failure to exclude bacteria and maintain CNS sterility, and subsequently through the active recruitment and/or failure to exclude circulating leukocytes. The interactions of SPN with these barriers, barrier inflammatory responses, along with their therapeutic implications, are explored in this review.

Assessment of Meningeal Lymphatics in the Parasagittal Dural Space: A Prospective Feasibility Study Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

Meningeal lymphatic vessels are predominantly located in the parasagittal dural space (PSD); these vessels drain interstitial fluids out of the brain and contribute to the glymphatic system. We aimed to investigate the ability of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing the dynamic changes in the meningeal lymphatic vessels in PSD. Eighteen participants (26-71 years; male:female, 10:8), without neurological or psychiatric diseases, were prospectively enrolled and underwent DCE-MRI. Three regions of interests (ROIs) were placed on the PSD, superior sagittal sinus (SSS), and cortical vein. Early and delayed enhancement patterns and six kinetic curve-derived parameters were obtained and compared between the three ROIs. Moreover, the participants were grouped into the young (< 65 years; n = 9) or older (≥ 65 years; n = 9) groups. Enhancement patterns and kinetic curve-derived parameters in the PSD were compared between the two groups. The PSD showed different enhancement patterns than the SSS and cortical veins (P < 0.001 and P < 0.001, respectively) in the early and delayed phases. The PSD showed slow early enhancement and a delayed wash-out pattern. The six kinetic curve-derived parameters of PSD was significantly different than that of the SSS and cortical vein. The PSD wash-out rate of older participants was significantly lower (median, 0.09; interquartile range [IQR], 0.01-0.15) than that of younger participants (median, 0.32; IQR, 0.07-0.45) (P = 0.040). This study shows that the dynamic changes of meningeal lymphatic vessels in PSD can be assessed with DCE-MRI, and the results are different from those of the venous structures. Our finding that delayed wash-out was more pronounced in the PSD of older participants suggests that aging may disturb the meningeal lymphatic drainage.

The lymphatic drainage systems in the brain: a novel target for ischemic stroke?

Recent studies have proposed three lymphatic drainage systems in the brain, that is, the glymphatic system, the intramural periarterial drainage pathway, and meningeal lymphatic vessels, whose roles in various neurological diseases have been widely explored. The glymphatic system is a fluid drainage and waste clearance pathway that utilizes perivascular space and aquaporin-4 protein located in the astrocyte endfeet to provide a space for exchange of cerebrospinal fluid and interstitial fluid. The intramural periarterial drainage pathway drives the flow of interstitial fluid through the capillary basement membrane and the arterial tunica media. Meningeal lymphatic vessels within the dura mater are involved in the removal of cerebral macromolecules and immune responses. After ischemic stroke, impairment of these systems could lead to cerebral edema, accumulation of toxic factors, and activation of neuroinflammation, while restoration of their normal functions can improve neurological outcomes. In this review, we summarize the basic concepts of these drainage systems, including drainage routes, physiological functions, regulatory mechanisms, and detection technologies. We also focus on the roles of lymphatic drainage systems in brain injury after ischemic stroke, as well as recent advances in therapeutic strategies targeting these drainage systems. These findings provide information for potential novel strategies for treatment of stroke.

Characteristic Features of Deep Brain Lymphatic Vessels and Their Regulation by Chronic Stress.

Studies have demonstrated that a functional network of meningeal lymphatic vessels exists in the brain. However, it is unknown whether lymphatic vessels could also extend deep into the brain parenchyma and whether the vessels could be regulated by stressful life events. We used tissue clearing techniques, immunostaining, light-sheet whole-brain imaging, confocal imaging in thick brain sections and flow cytometry to demonstrate the existence of lymphatic vessels deep in the brain parenchyma. Chronic unpredictable mild stress or chronic corticosterone treatment was used to examine the regulation of brain lymphatic vessels by stressful events. Western blotting and coimmunoprecipitation were used to provide mechanistic insights. We demonstrated the existence of lymphatic vessels deep in the brain parenchyma and characterized their features in the cortex, cerebellum, hippocampus, midbrain, and brainstem. Furthermore, we showed that deep brain lymphatic vessels can be regulated by stressful life events. Chronic stress reduced the length and areas of lymphatic vessels in the hippocampus and thalamus but increased the diameter of lymphatic vessels in the amygdala. No changes were observed in prefrontal cortex, lateral habenula, or dorsal raphe nucleus. Chronic corticosterone treatment reduced lymphatic endothelial cell markers in the hippocampus. Mechanistically, chronic stress might reduce hippocampal lymphatic vessels by down-regulating vascular endothelial growth factor C receptors and up-regulating vascular endothelial growth factor C neutralization mechanisms. Our results provide new insights into the characteristic features of deep brain lymphatic vessels, as well as their regulation by stressful life events.

Acquired immunity and Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive defects. The role of the central immune system dominated by microglia in the progression of AD has been extensively investigated. However, little is known about the peripheral immune system in AD pathogenesis. Recently, with the discovery of the meningeal lymphatic vessels and glymphatic system, the roles of the acquired immunity in the maintenance of central homeostasis and neurodegenerative diseases have attracted an increasing attention. The T cells not only regulate the function of neurons, astrocytes, microglia, oligodendrocytes and brain microvascular endothelial cells, but also participate in the clearance of β-amyloid (Aβ) plaques. Apart from producing antibodies to bind Aβ peptides, the B cells affect Aβ-related cascades via a variety of antibody-independent mechanisms. This review systemically summarizes the recent progress in understanding pathophysiological roles of the T cells and B cells in AD.

Delivery of Biomimetic Liposomes via Meningeal Lymphatic Vessels Route for Targeted Therapy of Parkinson's Disease.

Targeted therapy of Parkinson's disease is an important challenge because of the blood-brain barrier limitation. Here, we propose a natural killer cell membrane biomimetic nanocomplex (named BLIPO-CUR) delivered via the meningeal lymphatic vessel (MLV) route to further the therapeutic efficacy of Parkinson's disease. The membrane incorporation enables BLIPO-CUR to target the damaged neurons, thus improving their therapeutic efficacy through clearing reactive oxygen species, suppressing the aggregation of α-synuclein, and inhibiting the spread of excess α-synuclein species. Compared with the conventional intravenous injection, this MLV administration can enhance the delivered efficiency of curcumin into the brain by ~20 folds. The MLV route administration of BLIPO-CUR enhances the treatment efficacy of Parkinson's disease in mouse models by improving their movement disorders and reversing neuron death. Our findings highlight the great potential of MLV route administration used as targeted delivery of drugs to the brain, holding a great promise for neurodegenerative disease therapy.

Neuroimaging is the new "spatial omic": multi-omic approaches to neuro-inflammation and immuno-thrombosis in acute ischemic stroke.

Ischemic stroke (IS) is the leading cause of acquired disability and the second leading cause of dementia and mortality. Current treatments for IS are primarily focused on revascularization of the occluded artery. However, only 10% of patients are eligible for revascularization and 50% of revascularized patients remain disabled at 3 months. Accumulating evidence highlight the prognostic significance of the neuro- and thrombo-inflammatory response after IS. However, several randomized trials of promising immunosuppressive or immunomodulatory drugs failed to show positive results. Insufficient understanding of inter-patient variability in the cellular, functional, and spatial organization of the inflammatory response to IS likely contributed to the failure to translate preclinical findings into successful clinical trials. The inflammatory response to IS involves complex interactions between neuronal, glial, and immune cell subsets across multiple immunological compartments, including the blood-brain barrier, the meningeal lymphatic vessels, the choroid plexus, and the skull bone marrow. Here, we review the neuro- and thrombo-inflammatory responses to IS. We discuss how clinical imaging and single-cell omic technologies have refined our understanding of the spatial organization of pathobiological processes driving clinical outcomes in patients with an IS. We also introduce recent developments in machine learning statistical methods for the integration of multi-omic data (biological and radiological) to identify patient-specific inflammatory states predictive of IS clinical outcomes.

Borneol-driven meningeal lymphatic drainage clears amyloid-β peptide to attenuate Alzheimer-like phenotype in mice.

Rationale: The accumulation and clearance of amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD). The (re)discovery of meningeal lymphatic vessels in recent years has focused attention on the lymphatic clearance of Aβ and has become a promising therapeutic target for such diseases. However, there is a lack of small molecular compounds that could clearly regulate meningeal lymphatic drainage to remove Aβ from the brain. Methods: We investigated the effect of borneol on meningeal lymphatic clearance of macromolecules with different molecular weights (including Aβ) in the brain. To further investigate the mechanism of borneol regulating meningeal lymphatic drainage, immunofluorescence staining, western blotting, ELISA, RT-qPCR, and Nitric Oxide assay kits were used. The cognitive function of AD mice after borneol treatment was evaluated using two behavioral tests: open field (OF) and Morris water maze (MWM). Results: This study discovered that borneol could accelerate the lymphatic clearance of Aβ from the brain by enhancing meningeal lymphatic drainage. Preliminary mechanism analysis revealed that borneol could improve the permeability and inner diameter of lymphatic vessels, allowing macromolecules to drain into the cervical lymph nodes (CLNS) and then be transported to the lymphatic circulation. To speed up the clearance of macromolecules, borneol also stimulated lymphatic constriction by lowering the level of nitric oxide in the meninges. In addition, borneol stimulated lymphangiogenesis by increasing the levels of FOXC2, VEGFC, and LYVE-1 in the meninges, which promoted the clearance rates of macromolecules. Borneol improved meningeal lymphatic clearance not only for Aβ but also for other macromolecular polymers (molecular weight in the range of 2 KD - 45 KD. Borneol ameliorated cognitive deficits and alleviated brain Aβ burden in Aβ-injected mice. Conclusions: Our findings not only provide a strategy to regulate lymphatic clearance pathways of macromolecules in the brain, but also new targets and ideas for treating neurodegenerative diseases like AD. Furthermore, our findings indicate that borneol is a promising therapeutic drug for AD.

LYMPHATIC DRAINAGE SYSTEM OF THE BRAIN: A NEW PLAYER IN NEUROSCIENCE

The lymphatic system not only plays an important role as a drainage eliminating metabolic wastes and toxins from tissues, but also represents an arena for the unfolding of immune response scenarios aimed at protecting the organism from bacteria and viruses. In the central nervous system (CNS), drainage processes proceed with the same intensity as in peripheral tissues. The brain actively exchanges nutrients with the blood and excretes metabolic waste products through the drainage paths closely related to the peripheral lymphatic system. The same routes allow the traffic of immune cells and antibodies to the CNS, thus providing a communication between the peripheral and central immune systems. Over the two-century history of brain drainage studies, a lot of facts have been accumulated to suggest indirectly the presence of lymphatic vessels in the CNS. However, even with the advent of high-tech imaging of brain structures and a rediscovery of the meningeal lymphatic vessels (MLVs), which was a watershed in neuroscience, scientists have not advanced beyond4 confirming the already existing dogma that the lymphatic network is present exclusively in the brain meninges, but not in brain tissues. In fact, however, the rediscovery of MLVs by American scientists was not a “true revelation”, as they were first described by the Italian anatomist Mascagni two centuries earlier, and his results were confirmed later on in many other studies performed on the meninges in humans, macaques, rodents, dogs, rabbits and zebrafish. As a result, the scientific community did not recognize the “forgotten” MLVs as a new discovery. This review highlights the turning points that occurred in neuroscience, when a new player has entered the game and set in order bicentennial efforts of scientists to explain how unnecessary molecules and toxins are removed from the brain, as well as how drainage and immunity are implemented in the CNS. This is an important informational and creative platform both for new fundamental knowledge about the lymphatic system in the brain, as well as for the development of innovative neurorehabilitation technologies based on the management of lymphatic drainage processes.

Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain.

The discovery of meningeal lymphatic vessels that drain the central nervous system (CNS) has prompted new insights into how immune responses develop in the brain. In this study, we examined how T cell responses against CNS-derived antigen develop in the context of infection. We found that meningeal lymphatic drainage promotes CD4+ and CD8+ T cell responses against the neurotropic parasite Toxoplasma gondii in mice, and we observed changes in the dendritic cell compartment of the dural meninges that may support this process. Indeed, we found that mice chronically, but not acutely, infected with T. gondii exhibited a significant expansion and activation of type 1 and type 2 conventional dendritic cells (cDC) in the dural meninges. cDC1s and cDC2s were both capable of sampling cerebrospinal fluid (CSF)-derived protein and were found to harbor processed CSF-derived protein in the draining deep cervical lymph nodes. Disrupting meningeal lymphatic drainage via ligation surgery led to a reduction in CD103+ cDC1 and cDC2 number in the deep cervical lymph nodes and caused an impairment in cDC1 and cDC2 maturation. Concomitantly, lymphatic vessel ligation impaired CD4+ and CD8+ T cell activation, proliferation, and IFN‑γ production at this site. Surprisingly, however, parasite-specific T cell responses in the brain remained intact following ligation, which may be due to concurrent activation of T cells at non-CNS-draining sites during chronic infection. Collectively, our work reveals that CNS lymphatic drainage supports the development of peripheral T cell responses against T. gondii but remains dispensable for immune protection of the brain.

Leptomeningeal amyloidosis: features of the clinical picture (clinical observation)

Hereditary transthyretin amyloidosis belongs to a group of diseases with an autosomal dominant type of transmission and a heterogeneous clinical picture, which depends on the type of transthyretin gene mutation. The leptomeningeal form is a rare phenotypic variant of amyloidosis with a predominant involvement of brain and spinal cord meninges, as well as cortical meningeal vessels. The main manifestations of this phenotype include cephalalgic syndrome, episodes of acute cerebrovascular accident, hearing impairment, epileptic seizures, progressive cognitive impairment reaching the degree of dementia, impaired consciousness, etc. The article describes a clinical case of revealing of amyloidogenic mutation Ala45Thr with a hereditary family history and typical manifestations of leptomeningeal amyloidosis at the onset of the disease, as well as impaired renal function. Neuroimaging with contrast enhancement revealed a characteristic thickening of the meninges of the spinal cord due to the deposition of amyloid masses.

Lymphatic drainage at the meningeal‐brain interface in aging and Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent form of dementia. We have recently shown that proper meningeal lymphatic drainage is important for brain fluid flow, learning and memory in aging and for brain amyloid beta (Aβ) clearance in mouse models of AD. Interestingly, genetic factors that increased the risk for AD are also linked to altered meningeal lymphatic function.MethodMeningeal lymphatic function was evaluated in mouse models of AD at different ages by RNA sequencing of sorted meningeal lymphatic endothelial cells (LECs) and by assessing of lymphatic vessel morphology and drainage capacity. Meningeal lymphatic dysfunction was induced by photoablation, whereas enhancement of meningeal lymphatic drainage was achieved by increasing the levels of VEGF‐C. The transcriptional signatures of brain blood endothelial cells and microglia were determined by single‐cell RNA sequencing upon manipulation of meningeal lymphatic drainage. Changes in Aβ plaque clearance by monoclonal antibodies were assessed upon prolonged manipulation of meningeal lymphatic drainage. Integrated analysis was performed using murine and human cell RNA‐seq data, as well as AD summary statistics.ResultWe show that a progressive deposition of meningeal Aβ with aging leads to gene expression changes in meningeal lymphatic endothelial cells and an accelerated reduction in meningeal lymphatic vessel coverage in the 5xFAD mouse model. Interestingly, modulating meningeal lymphatic function in AD transgenic mice affects the clearance of Aβ by monoclonal antibodies, a feature that is closely associated with the activation signatures in brain blood endothelial cells and microglia. Furthermore, genes that are highly expressed in lymphatic vasculature are associated with increased risk for AD and altered levels of Aβ in the CSF of AD patients. Integrated analysis of murine and human microglia transcriptomes revealed an association between the signatures of activated microglia from mice with defective meningeal lymphatic function and activated microglia isolated from the AD brain. We are now turning our attention to the interaction between the main genetic risk factor for AD, expression of the apolipoprotein E4, and changes in brain drainage by the meningeal lymphatic vascular system.ConclusionCollectively, our data underline the notion that a dysfunctional meningeal lymphatic vasculature may impact on AD pathophysiology and therapeutic outcome.

Belgian Carriers of Rare ABCA7 Mutations Present with Pronounced Cerebral Amyloid Angiopathy and Alzheimer’s Disease

AbstractBackground ABCA7 is a major risk gene for Alzheimer’s disease (AD) and rare premature termination codon (PTC) and missense mutations are enriched in AD patients. In preliminary studies we obtained that ABCA7 PTC and missense mutation carriers present with a classic AD phenotype, but severe levels of cerebral amyloid angiopathy (CAA) were also found (table 1, figures 1‐2). We aim to delineate the clinicopathological phenotype of rare ABCA7 mutation carriers in Belgian CAA patients.MethodsGenetic screening of ABCA7 in a Belgian CAA cohort (n = 83), with genotype‐phenotype comparison of the ABCA7 carriers using demographics and clinicopathology data.ResultsIn 21.4% (18/84) of CAA patients a rare ABCA7 mutation was identified. Seven patients carried a PTC mutation, 10 a rare missense variant, and in one CAA patient we found a deletion. The mean onset age was 66.4±12.8 (range 47‐84) years, while the mean age at death was 68.0±10.3 (range 48‐92) years. In 87.5% (7/8) of patients a positive family history of disease was mentioned. Cognitive decline was present in 52.9% (9/17). Nine patients were diagnosed as probable CAA, and four as possible CAA. In six patients postmortem examination showed moderate‐to‐severe levels of CAA in all but one patient (83.3%, 5/6) and AD neuropathological hallmarks (100%, 6/6). Extensive levels of CAA were present in both the meningeal and capillary blood vessels, and moderate to high levels of CAA in the parenchymal blood vessels (Figure 3).ConclusionsOur data suggests that rare ABCA7 mutations are frequently present in CAA patients. Carriers show signs of severe levels of CAA, as well as AD neuropathological hallmarks. The findings of this study have important implications for future research and clinical practice.

Topographic and Morphometric Study of the Foramen Spinosum of the Skull and Its Clinical Correlation.

Background and Objectives: The spinous foramen (FS) of the skull is an opening located in the greater wing of the sphenoid bone at the base of the skull, and it includes the middle meningeal vessels and the meningeal branch of the mandibular trigeminal nerve. The FS is commonly used as an anatomical landmark in neurosurgical procedures and neuroimaging of the middle cranial fossa because of its relationship with other cranial foramina and surrounding vascular and nervous structures. Thus, specific knowledge of its topography and possible anatomical variations is important regarding some surgical interventions and skull imaging. The aim of this study was to provide further details on the morphology of the FS of the skull by evaluating its topographic and morphometric relationships and correlating the findings with clinical practice. Materials and Methods: Thirty dried skulls of human skeletons from body donors from the collection of the Laboratory of Anatomical Microdissection at a medical school were used. The metric dimensions and variations of the FS and its relationship with adjacent bone structures were analyzed with an interface digital microscope. Results: The results showed the bilateral presence of the FS in all skulls; however, differences were observed in the shape, diameter, and topography in relation to the foramen ovale and the spine of the sphenoid. The FS was present in the greater wing of the sphenoid bone; however, in one skull, it was located in the lateral lamina of the pterygoid process. The FS was smaller than the foramen ovale. A round and oval FS shape was the most common (42.1% and 32.8% of the samples, respectively), followed by drop-shaped (12.5%) and irregular-shaped (12.5%) foramina. Conclusions: In conclusion, FS variations among individuals are common and must be considered by surgeons during skull base interventions in order to avoid accidents and postoperative complications.

Photodynamic Opening of the Blood-Brain Barrier and the Meningeal Lymphatic System: The New Niche in Immunotherapy for Brain Tumors.

Photodynamic therapy (PDT) is a promising add-on therapy to the current standard of care for patients with glioblastoma (GBM). The traditional explanation of the anti-cancer PDT effects involves the PDT-induced generation of a singlet oxygen in the GBM cells, which causes tumor cell death and microvasculature collapse. Recently, new vascular mechanisms of PDT associated with opening of the blood-brain barrier (OBBB) and the activation of functions of the meningeal lymphatic vessels have been discovered. In this review, we highlight the emerging trends and future promises of immunotherapy for brain tumors and discuss PDT-OBBB as a new niche and an important informative platform for the development of innovative pharmacological strategies for the modulation of brain tumor immunity and the improvement of immunotherapy for GBM.

Progress on Brain and Ocular Lymphatic System.

In recent years, 2 major discoveries have modified the traditional understanding of the brain. First, meningeal lymphatic vessels (MLV) were found in the dural sinus, which may absorb and drain cerebrospinal fluid (CSF). Second, the glymphatic system was discovered, composed of para-arterial CSF influx channel, paravenous interstitial fluid (ISF) efflux channel, and the water channel aquaporin-4 (AQP4) in astrocytes connecting the 2 channels. Accumulating evidence demonstrates that the lymphatic system of the brain plays a vital role within the circulation of CSF and, therefore, in the removal of metabolites. Therefore, it is involved in the incidence and development of some central nervous system (CNS) diseases. The optic nerve and retina are the extension of the CNS in the orbit. Whether they have a lymphatic system and how they clear the metabolites of the optic nerve and retina are still unclear. Recent studies have found that the ocular lymphatic system has a crucial impact on bounding eye diseases, like disorders of the optic nerve and retina. Therefore, here we review the recent research progress concerning the structure and function of MLV and glymphatic system. We also discuss the biomarkers for identification of lymphatic vessels, the composition of ocular lymphatic systems, and the possible association with diseases.