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      Mapping the Glymphatic Pathway Using Imaging Advances

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          Abstract

          The glymphatic system is a newly discovered waste-clearing system that is analogous to the lymphatic system in our central nervous system. Furthermore, disruption in the glymphatic system has also been associated with many neurodegenerative disorders (e.g., Alzheimer’s disease), traumatic brain injury, and subarachnoid hemorrhage. Thus, understanding the function and structure of this system can play a key role in researching the progression and prognoses of these diseases. In this review article, we discuss the current ways to map the glymphatic system and address the advances being made in preclinical mapping. As mentioned, the concept of the glymphatic system is relatively new, and thus, more research needs to be conducted in order to therapeutically intervene via this system.

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          Most cited references77

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          Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

          Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.
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            A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

            Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.
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              Sleep drives metabolite clearance from the adult brain.

              The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
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                Author and article information

                Journal
                101751012
                48769
                J (Basel)
                J (Basel)
                J
                2571-8800
                14 August 2023
                September 2023
                08 August 2023
                01 September 2023
                : 6
                : 3
                : 477-491
                Affiliations
                [1 ]College of Medicine, University of Florida, Gainesville, FL 32610, USA
                [2 ]College of Medicine, Florida International University, Miami, FL 33199, USA
                [3 ]Thermo Fisher Scientific Inc., Boston, MA 02210, USA
                [4 ]Department of Neurosurgery, University of Florida, 1600 SW Archer Rd., Gainesville, FL 32610, USA
                Author notes

                Author Contributions: Conceptualization, B.L.-W.; Writing—original draft preparation, R.N.T., I.P.K., I.G., D.T.F., P.S. and E.M.V.; Writing—reviewing & editing, R.N.T., I.P.K., I.G., D.T.F., P.S. and E.M.V. All authors have read and agreed to the published version of the manuscript.

                Article
                NIHMS1923820
                10.3390/j6030031
                10439810
                37601813
                2d2002a5-5ddf-47cb-9bfb-4a8c1427a218

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                Categories
                Article

                glymphatic system,magnetic resonance imaging (mri) sequencing,imaging techniques,neurological diseases

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