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      Dynamic Evolution of the Glymphatic System at the Early Stages of Subarachnoid Hemorrhage


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          The early stages of subarachnoid hemorrhage (SAH) are extremely important for the progression and prognosis of this disease. The glymphatic system (GS) has positive implications for the nervous system due to its ability to clearance tau and amyloid-β (Aβ) protein. Previous studies have shown that GS dysfunction will appear after SAH. However, there is no systematic evaluation of the degree of damage and development process of GS function in the early stage after SAH. In this study, we evaluated the GS function and neurobehavioral in the sham, 6 h, 1, 3, and 7 days after SAH, respectively. Our results showed that the function of GS was severely attenuated in mice after SAH with a decreased polarity of Aquaporin-4 (AQP4), increased expression of AQP4, a linear correlation with the dystrophin-associated complex (DAC), the proliferation of reactive astrocytes, increased tau protein accumulation, and decreased neurological function. Collectively, these findings provide a comprehensive understanding of the functional changes of GS after SAH, provide references for subsequent scholars studying SAH, and suggest some potential mechanistic insight that affects AQP4 polarity and GS function.

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          Most cited references42

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          Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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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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              Impairment of paravascular clearance pathways in the aging brain.

              In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain.

                Author and article information

                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                01 July 2022
                : 13
                : 924080
                [1] 1Department of Neurosurgery, Tianjin Medical University General Hospital , Tianjin, China
                [2] 2Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School , Nanjing, China
                [3] 3Department of Neurosurgery, Beijing Friendship Hospital, Capital Medical University , Beijing, China
                [4] 4Department of Radiology, The Affiliated Suzhou Hospital of Nanjing Medical University , Suzhou, China
                [5] 5Department of Neurosurgery, Tianjin Fifth Central Hospital , Tianjin, China
                Author notes

                Edited by: Xin Cheng, Fudan University, China

                Reviewed by: Xiaoyu Wang, Zhejiang University, China; Feng Han, The Pennsylvania State University (PSU), United States; Yameng Gu, The Ohio State University, United States

                *Correspondence: Xinyu Yang yangxinyu@ 123456tmu.edu.cn

                This article was submitted to Stroke, a section of the journal Frontiers in Neurology

                †These authors have contributed equally to this work and share first authorship

                Copyright © 2022 Hou, Li, Wang, Liu, Zhao, Zhang, Wang, Ren, Cui and Yang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 20 April 2022
                : 06 June 2022
                Page count
                Figures: 8, Tables: 1, Equations: 0, References: 42, Pages: 15, Words: 8605
                Funded by: Natural Science Foundation of Tianjin City, doi 10.13039/501100006606;
                Original Research

                glymphatic system,subarachnoid hemorrhage,dynamic evolution,aqp4,dystrophin-associated complex


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