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      Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI


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          Here, we report the existence of meningeal lymphatic vessels in human and nonhuman primates (common marmoset monkeys) and the feasibility of noninvasively imaging and mapping them in vivo with high-resolution, clinical MRI. On T2-FLAIR and T1-weighted black-blood imaging, lymphatic vessels enhance with gadobutrol, a gadolinium-based contrast agent with high propensity to extravasate across a permeable capillary endothelial barrier, but not with gadofosveset, a blood-pool contrast agent. The topography of these vessels, running alongside dural venous sinuses, recapitulates the meningeal lymphatic system of rodents. In primates, meningeal lymphatics display a typical panel of lymphatic endothelial markers by immunohistochemistry. This discovery holds promise for better understanding the normal physiology of lymphatic drainage from the central nervous system and potential aberrations in neurological diseases.

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          How does the brain rid itself of waste products? Other organs in the body achieve this via a system called the lymphatic system. A network of lymphatic vessels extends throughout the body in a pattern similar to that of blood vessels. Waste products from cells, plus bacteria, viruses and excess fluids drain out of the body’s tissues into lymphatic vessels, which transfer them to the bloodstream. Blood vessels then carry the waste products to the kidneys, which filter them out for excretion. Lymphatic vessels are also a highway for circulation of white blood cells, which fight infections, and are therefore an important part of the immune system.

          Unlike other organs, the brain does not contain lymphatic vessels. So how does it remove waste? Some of the brain’s waste products enter the fluid that bathes and protects the brain – the cerebrospinal fluid – before being disposed of via the bloodstream. However, recent studies in rodents have also shown the presence of lymphatic vessels inside the outer membrane surrounding the brain, the dura mater.

          Absinta, Ha et al. now show that the dura mater of people and marmoset monkeys contains lymphatic vessels too. Spotting lymphatic vessels is challenging because they resemble blood vessels, which are much more numerous. In addition, Absinta, Ha et al. found a way to visualize the lymphatic vessels in the dura mater using brain magnetic resonance imaging, and could confirm that lymphatic vessels are present in autopsy tissue using special staining methods.

          For magnetic resonance imaging, monkeys and human volunteers received an injection of a dye-like substance called gadolinium, which travels via the bloodstream to the brain. In the dura mater, gadolinium leaks out of blood vessels and collects inside lymphatic vessels, which show up as bright white areas on brain scans. To confirm that the white areas were lymphatic vessels, the experiment was repeated using a different dye that does not leak out of blood vessels. As expected, the signals observed in the previous brain scans did not appear.

          By visualizing the lymphatic system, this technique makes it possible to study how the brain removes waste products and circulates white blood cells, and to examine whether this process is impaired in aging or disease.

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          Most cited references15

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          Brain-wide pathway for waste clearance captured by contrast-enhanced MRI.

          The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer's disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer's disease susceptibility and progression in the live human brain.
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            Intracranial Vessel Wall MRI: Principles and Expert Consensus Recommendations of the American Society of Neuroradiology.

            Intracranial vessel wall MR imaging is an adjunct to conventional angiographic imaging with CTA, MRA, or DSA. The technique has multiple potential uses in the context of ischemic stroke and intracranial hemorrhage. There remain gaps in our understanding of intracranial vessel wall MR imaging findings and research is ongoing, but the technique is already used on a clinical basis at many centers. This article, on behalf of the Vessel Wall Imaging Study Group of the American Society of Neuroradiology, provides expert consensus recommendations for current clinical practice.
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              Lymphatic drainage of the brain and the pathophysiology of neurological disease.

              There are no conventional lymphatics in the brain but physiological studies have revealed a substantial and immunologically significant lymphatic drainage from brain to cervical lymph nodes. Cerebrospinal fluid drains via the cribriform plate and nasal mucosa to cervical lymph nodes in rats and sheep and to a lesser extent in humans. More significant for a range of human neurological disorders is the lymphatic drainage of interstitial fluid (ISF) and solutes from brain parenchyma along capillary and artery walls. Tracers injected into grey matter, drain out of the brain along basement membranes in the walls of capillaries and cerebral arteries. Lymphatic drainage of antigens from the brain by this route may play a significant role in the immune response in virus infections, experimental autoimmune encephalomyelitis and multiple sclerosis. Neither antigen-presenting cells nor lymphocytes drain to lymph nodes by the perivascular route and this may be a factor in immunological privilege of the brain. Vessel pulsations appear to be the driving force for the lymphatic drainage along artery walls, and as vessels stiffen with age, amyloid peptides deposit in the drainage pathways as cerebral amyloid angiopathy (CAA). Blockage of lymphatic drainage of ISF and solutes from the brain by CAA may result in loss of homeostasis of the neuronal environment that may contribute to neuronal malfunction and dementia. Facilitating perivascular lymphatic drainage of amyloid-beta (Abeta) in the elderly may prevent the accumulation of Abeta in the brain, maintain homeostasis and provide a therapeutic strategy to help avert cognitive decline in Alzheimer's disease.

                Author and article information

                Role: Reviewing Editor
                eLife Sciences Publications, Ltd
                03 October 2017
                : 6
                : e29738
                [1 ]deptTranslational Neuroradiology Section National Institute of Neurological Disorders and Stroke, National Institutes of Health BethesdaUnited States
                [2 ]deptHematopathology Section, Laboratory of Pathology National Cancer Institute, National Institutes of Health BethesdaUnited States
                [3 ]deptCenter for Brain Immunology and Glia, Department of Neuroscience, School of Medicine University of Virginia CharlottesvilleUnited States
                [4 ]deptSurgical Neurology Branch National Institute of Neurological Disorders and Stroke, National Institutes of Health BethesdaUnited States
                University of Oxford United Kingdom
                University of Oxford United Kingdom
                Author notes

                These authors contributed equally to this work.

                Author information

                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                : 19 June 2017
                : 01 September 2017
                Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;
                Award ID: Intramural Research Program
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000890, National Multiple Sclerosis Society;
                Award ID: Postdoctoral Fellowship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000910, Conrad N. Hilton Foundation;
                Award ID: Marilyn Hilton Award for Innovation in Multiple Sclerosis Research
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: Intramural Research Program
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;
                Award ID: R01AG034113
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100006542, Lymphatic Education and Research Network;
                Award ID: Postdoctoral fellowship
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Short Report
                Human Biology and Medicine
                Custom metadata
                Meningeal lymphatic vessels are present in human and nonhuman primates (common marmoset monkeys) and they can be noninvasively imaged and mapped in vivo with high-resolution, clinical MRI.

                Life sciences
                marmoset monkey,lymphatics,mri,meninges,human,other
                Life sciences
                marmoset monkey, lymphatics, mri, meninges, human, other


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