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      Circadian therapy interventions for glymphatic dysfunction in concussions injuries: A narrative review


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          There are two primary threats to the brain after concussion. The first is a buildup of neurotoxic proteins in the brain. The second, a partial consequence of the first, is a sustained neuroinflammatory response that may lead to central sensitization and the development of persistent post-concussive symptoms. These threats make neurotoxin clearance a high clinical priority in the acute period after injury. The glymphatic system is the brain's primary mechanism for clearing neurotoxic waste. The glymphatic system is intimately tied to the sleep cycle and circadian dynamics. However, glymphatic dysfunction and sleep disturbances are nearly ubiquitous in the acute period after concussion injury. Because of this, sleep optimization via circadian therapy is a time-sensitive and critical tool in acute concussion management.

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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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              Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury.

              Traumatic brain injury (TBI) is an established risk factor for the early development of dementia, including Alzheimer's disease, and the post-traumatic brain frequently exhibits neurofibrillary tangles comprised of aggregates of the protein tau. We have recently defined a brain-wide network of paravascular channels, termed the "glymphatic" pathway, along which CSF moves into and through the brain parenchyma, facilitating the clearance of interstitial solutes, including amyloid-β, from the brain. Here we demonstrate in mice that extracellular tau is cleared from the brain along these paravascular pathways. After TBI, glymphatic pathway function was reduced by ∼60%, with this impairment persisting for at least 1 month post injury. Genetic knock-out of the gene encoding the astroglial water channel aquaporin-4, which is importantly involved in paravascular interstitial solute clearance, exacerbated glymphatic pathway dysfunction after TBI and promoted the development of neurofibrillary pathology and neurodegeneration in the post-traumatic brain. These findings suggest that chronic impairment of glymphatic pathway function after TBI may be a key factor that renders the post-traumatic brain vulnerable to tau aggregation and the onset of neurodegeneration.

                Author and article information

                Sci Prog
                Sci Prog
                Science Progress
                SAGE Publications (Sage UK: London, England )
                27 July 2023
                Jul-Sep 2023
                : 106
                : 3
                : 00368504231189536
                [1 ]Neurosurgical Medical Clinic, San Diego, CA, USA
                [2 ]TBI Virtual, San Diego, CA, USA
                [3 ]Ringgold 8788, universityDepartment of Otolaryngology-Head and Neck Surgery, University of California, Irvine; , CA, USA
                Author notes
                [*]John Francis, TBI Virtual, San Diego, 515 N Hwy 101, Solana Beach, CA 92075, USA. Email: john@ 123456tbivirtual.com
                Author information
                © The Author(s) 2023

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                Medicine & Health Sciences
                Sports and Exercise Medicine
                Custom metadata
                July-September 2023

                sleep,glymphatic system,brain injuries,traumatic,brain concussion,melatonin,circadian rhythm


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