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      Hypothermia reduces glymphatic transportation in traumatic edematous brain assessed by intrathecal dynamic contrast-enhanced MRI


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          The glymphatic system has recently been shown to clear brain extracellular solutes and can be extensively impaired after traumatic brain injury (TBI). Despite hypothermia being identified as a protective method for the injured brain via minimizing the formation of edema in the animal study, little is known about how hypothermia affects the glymphatic system following TBI. We use dynamic contrast-enhanced MRI (DCE-MRI) following cisterna magna infusion with a low molecular weight contrast agent to track glymphatic transport in male Sprague–Dawley rats following TBI with hypothermia treatment and use diffusion-weighted imaging (DWI) sequence to identify edema after TBI, and further distinguish between vasogenic and cytotoxic edema. We found that hypothermia could attenuate brain edema, as demonstrated by smaller injured lesions and less vasogenic edema in most brain subregions. However, in contrast to reducing cerebral edema, hypothermia exacerbated the reduction of efficiency of glymphatic transportation after TBI. This deterioration of glymphatic drainage was present brain-wide and showed hemispherical asymmetry and regional heterogeneity across the brain, associated with vasogenic edema. Moreover, our data show that glymphatic transport reduction and vasogenic edema are closely related to reducing perivascular aquaporin-4 (AQP 4) expression. The suppression of glymphatic transportation might eliminate the benefits of brain edema reduction induced by hypothermia and provide an alternative pathophysiological factor indicating injury to the brain after TBI. Thus, this study poses a novel emphasis on the potential role of hypothermia in managing severe TBI.

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          Most cited references40

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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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              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.

                Author and article information

                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                20 October 2022
                : 13
                : 957055
                [1] 1Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University , Shanghai, China
                [2] 2Department of Radiology, Affiliated Zhoupu Hospital, Shanghai University of Medicine and Health Sciences , Shanghai, China
                [3] 3Department of Radiology, Charité-Universitätsmedizin Berlin , Berlin, Germany
                [4] 4Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China
                [5] 5Department of Radiology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China
                [6] 6Shanghai Wei Yu International School , Shanghai, China
                [7] 7Department of Radiology, Affiliated Sixth People's Hospital, Shanghai Jiao Tong University , Shanghai, China
                [8] 8Department of Radiology, Shanghai East Hospital Tongji University , Shanghai, China
                Author notes

                Edited by: Brandon Peter Lucke-Wold, University of Florida, United States

                Reviewed by: Eiichi Suehiro, International University of Health and Welfare, Narita, Japan; Victor G. J. Rodgers, University of California, Riverside, United States

                *Correspondence: Qing Lu Drluqingsjtu@ 123456163.com

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

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

                Copyright © 2022 Bai, Yuan, Mi, Zhang, Liu, Lu, Bao, Li and Lu.

                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.

                : 30 May 2022
                : 03 October 2022
                Page count
                Figures: 12, Tables: 3, Equations: 3, References: 40, Pages: 16, Words: 8412
                Original Research

                hypothermia,glymphatic function,traumatic brain injury,brain edema,dce-mri,diffusion-weighted imaging (dwi)


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