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      Clinical Interventions in Aging (submit here)

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      The Pathogenesis Based on the Glymphatic System, Diagnosis, and Treatment of Idiopathic Normal Pressure Hydrocephalus


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          Idiopathic normal pressure hydrocephalus (iNPH) is a rare neurological disorder with no clear prevalence factors and is a significant danger to the elderly. The intracranial glymphatic system is the internal environment that maintains brain survival and metabolism, and thus fluid exchange changes in the glymphatic system under various pathological conditions can provide important insights into the pathogenesis and differential diagnosis of many neurodegenerative diseases such as iNPH. iNPH can be diagnosed using a combination of clinical symptoms, imaging findings and history, and cerebrospinal fluid biomarkers due to the glymphatic system disorder. However, only few researchers have linked the two. Shunt surgery can improve the glymphatic system disorders in iNPH patients, and the surgical approach is determined using a combination of clinical diagnosis and trials. Therefore, we have composed this review to provide a future opportunity for elucidating the pathogenesis of iNPH based on the glymphatic system, and link the glymphatic system to the diagnosis and treatment of iNPH. The review will provide new insights into the medical research of iNPH.

          Most cited references133

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          Structural and functional features of central nervous system lymphatics

          One of the characteristics of the CNS is the lack of a classical lymphatic drainage system. Although it is now accepted that the CNS undergoes constant immune surveillance that takes place within the meningeal compartment 1–3 , the mechanisms governing the entrance and exit of immune cells from the CNS remain poorly understood 4–6 . In searching for T cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the CSF, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the CNS. The discovery of the CNS lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and shed new light on the etiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
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            The glymphatic pathway in neurological disorders

            Background The glial-lymphatic or glymphatic pathway is a fluid clearance pathway recently identified in the rodent brain. This pathway subserves the flow of cerebrospinal fluid (CSF) into the brain along arterial perivascular spaces and thence into the brain interstitium facilitated by aquaporin-4 (AQP4) water channels. The pathway then directs flows towards the venous perivascular and perineuronal spaces, ultimately clearing solutes from the neuropil into meningeal and cervical lymphatic drainage vessels. In rodents, the glymphatic pathway is primarily active during sleep, when the clearance of harmful metabolites such as amyloid β (Aβ) increases two-fold relative to the waking state. Glymphatic dysfunction has been demonstrated in animal models of traumatic brain injury (TBI), Alzheimer’s disease (AD) and micro-infarct disease, most likely in relation to perturbed expression of AQP4. The recent characterizations of the glymphatic and meningeal lymphatic systems calls for revaluation of the anatomical routes for CSF-ISF flow and the physiological role that these pathways play in CNS health. Recent developments Recent work has revealed that several features of the glymphatic and meningeal lymphatic systems are also present in humans. MRI imaging of intrathecally-administered contrast agent shows that CSF flows along pathways closely resembling the glymphatic system outlined in rodents. Furthermore, PET studies reveal that Aβ accumulates in the healthy brain after a single night of sleep deprivation, suggesting that the human glymphatic pathway might also be primarily active during sleep. Other PET studies have shown that CSF clearance of Aβ and tau tracers is reduced in patients with AD compared to healthy controls. The observed reduction in CSF clearance was associated with increasing grey matter Aβ levels in human brain, which is consistent with findings in mice showing that decreased glymphatic function leads Aβ accumulation. Altered AQP4 expression is also evident in brain tissue from AD or normal pressure hydrocephalus (NPH) patients; glymphatic MRI of NPH patients shows reduced CSF tracer entry and clearance. Where next? Future research is needed to confirm if specific factors driving glymphatic flow in rodents also apply to humans. Conducting longitudinal imaging studies to evaluate human CSF dynamics will determine if there is indeed a causal link between reduced brain solute clearance and the development of neurodegenerative diseases. Assessment of glymphatic function after stroke or TBI could identify if it correlates with neurological recovery. Gaining new insights into how behavior and genetics modify glymphatic function, and how this decompensates in disease should lead to the development of new preventive and diagnostic tools, as well as novel therapeutic targets.
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              Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI

              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.

                Author and article information

                Clin Interv Aging
                Clin Interv Aging
                Clinical Interventions in Aging
                15 January 2021
                : 16
                : 139-153
                [1 ]Department of Neurosurgery, Xiangya Hospital, Central South University , Changsha, Hunan 410008, People’s Republic of China
                [2 ]Diagnosis and Treatment Center for Hydrocephalus, Xiangya Hospital, Central South University , Changsha, Hunan 410008, People’s Republic of China
                [3 ]National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University , Changsha, Hunan 410008, People’s Republic of China
                [4 ]Pediatric Neurological Disease Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine , Shanghai 200092, People’s Republic of China
                [5 ]Department of Neurosurgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University , Changsha, Hunan 410013, People’s Republic of China
                Author notes
                Correspondence: Gelei Xiao Department of Neurosurgery, Xiangya Hospital, Central South University , Changsha, Hunan410008, People’s Republic of ChinaTel +8613707314060 Email xiaogelei@csu.edu.cn

                These authors contributed equally to this work

                © 2021 Tan et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                : 05 November 2020
                : 01 January 2021
                Page count
                Figures: 2, References: 133, Pages: 15

                Health & Social care
                idiopathic normal pressure hydrocephalus,glymphatic system,pathogenesis,diagnostic methods,shunt surgery


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