Glymphatic system

# Glymphatic system a network of vessels that clear waste from the central nervous system (CNS), mostly during sleep.  slide: https://hackmd.io/@patrickwu/talk20200521 images: http://tiny.cc/glymphaticsImages <aside class="notes"> The name "glymphatic system" was coined by the Danish neuroscientist Maiken Nedergaard in recognition of its dependence upon glial cells and the similarity of its functions to those of the peripheral lymphatic system. </aside> --- <img src="https://i.imgur.com/SsEtUpC.jpg" height="630" width="auto"></img> <aside class="notes"> The pathway starts with a para-arterial influx of cerebrospinal fluid (CSF) to the brain parenchyma, and then a clearance mechanism </aside> --- <iframe src="https://commons.wikimedia.org/wiki/File:Video_schematic_of_glymphatic_flow.ogv?embedplayer=yes" width="539.002770083" height="690" frameborder="0" ></iframe> <aside class="notes"> Exchange of solutes between CSF and ISF is driven primarily by arterial pulsation. Clearance is accomplished through convective bulk flow, facilitated by astrocytic aquaporin 4 water channels. </aside> --- ## **Aquaporin-4 (AQP4)** highly polarized to perivascular astrocytic endfeet (boundary of para-arterial CSF influx and the paravenous ISF clearance pathways) ---  ### CSF → brain parenchyma routes CSF rapidly enters the brain parenchyma by bulk flow via... * paravascular space around surface arteries * Virchow-Robin space <p> </br>  <aside class="notes"> 略 paravascular space around surface arteries and the Virchow-Robin space into which these penetrate comprise a physically and functionally distinct subcompartment through which CSF rapidly enters the brain parenchyma by bulk flow. This CSF flux is likely driven by arterial pulsation (13–15): the directionality of CSF influx into para-arterial spaces perhaps reflecting the differing pulse pressures between para-arterial and paravenous pathways </aside> --- <img src="https://i.imgur.com/SuvjeAw.jpg" height="630" height="auto"></img> --- ### Summary of Bulk flow * courses diffusely through brain tissue * pulsation-driven * Bulk flow ~~simple diffusion~~ → clearance (except > 32nm) * AQP4 helps * Immune surveillance without compromising CSF immune privilege (detect interstitial antigens delivered to the CSF by paravenous bulk outflow) --- ## <p style="line-height: 120%; font-size: 36px"><b>A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β</b></p> Sci Transl Med. 2012 Aug 15;4(147):147ra111. doi: 10.1126/scitranslmed.3003748. ---   <img src="https://i.imgur.com/t6Y1L3o.jpg"></img> --- <img src="https://i.imgur.com/00gLluX.png" height="630" width="auto"></img> ---  <img src="https://i.imgur.com/pMVYUDl.png" height="630" width=auto></img> --- ### Clearance route <table> <tr> <th>Conductor</th> <th>Primary route</th> </tr> <tr> <td>Some studies</td> <td>para-arterial sheaths</td> </tr> <tr> <td>This study</td> <td>paravenous pathways, particularly those surrounding the medial internal cerebral and caudal rhinal veins</td> </tr> </table> --- ### <p style="font-size:36px"><b>AQP4-dependent bulk flow not necessarily the terminal route for solute clearance from the cranium?</b></font> <font size="6"> <table> <tr><th>solutes location</th><th>clearance route</th></tr> <tr><td>solutes along the microvasculature and large draining veins</td><td>transport mechanisms at the BBB. </td></tr> <tr><td>solutes along the internal cerebral and caudal rhinal veins to their associated sinuses</td><td>bloodstream via arachnoid granulations</tr> </table> </font> ---  ### <p style="line-height:120%; font-size:48px;"><b>Parenchyma → nearest CSF compartment (if by mere simple diffusion)</b></p>  <table> <tr><td>urea (60 D): </td><td>5.4 hrs/cm</td></tr> <tr><td>albumin (66.5 kD): </td><td>109 hrs/cm</td></tr> </table> </p> ---  ## <p style="font-size:48px"><b>Sleep Drives Metabolite Clearance from the Adult Brain</b> Science. 2013 Oct 18; 342(6156): 0.1126/science.1241224. --- ### ↓NE → extracellular space increase → ↑bulk flow Awakeness: ↑NE ---  <img src="https://i.imgur.com/r2LQZiq.png" height="620px" width="auto"></img> ---  <img src="https://i.imgur.com/HvFH8rQ.png" height="620px" width="auto"></img> --- <img src="https://i.imgur.com/9KrlgBF.jpg" height="620px" width="auto"></img> ---  <img src="https://i.imgur.com/qXFw2UP.png" height="620px" width="auto"></img> --- <img src="https://i.imgur.com/KbZsta3.png" height="630" width="auto"></img> --- ### Conclusions * Glymphatic system contributes to the clearance of wastes in brain * AQP4 contributes to the convective bulk flow * Extracellular space enlarges at lower wakefulness, allowing more bulk flowcx