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Clearing Your Mind: A Glymphatic System?
Accepted Manuscript News Report: Clearing your mind: A Glymphatic System? Ferdinand K. Hui, MD. PII:
S1878-8750(15)00195-3
DOI:
10.1016/j.wneu.2015.03.001
Reference:
WNEU 2752
To appear in:
World Neurosurgery
Please cite this article as: Hui FK, News Report: Clearing your mind: A Glymphatic System?, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.03.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
News Report Clearing your mind: A Glymphatic System?
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The ubiquitous lymphatic system serves to move interstitial fluids back into the vascular system clearing extracellular proteins and excess fluid – ubiquitous except for one organ system: the brain. Schwalbe et al. [Schwalbe 1869] were the first to demonstrate a connection between the subarachnoid space and the lymphatic system in dogs and rabbits, however the precise route has been difficult to ascertain. Koh et al. demonstrated fluorescein tracer in olfactory and respiratory epithelium within 10 minutes of injection of the cisterna magna and proposed that one of the primary clearance mechanisms for cerebrospinal fluid (CSF) clearance is through the cribriform plate [Koh 2005]. Other recent work has similiarly postulated various mechanisms for CSF and lymphatic connection [Auckland, Abbott]
M AN U
However, more recent work [Iliff 2012, Iliff 2013] has defined a brain wide anatomic pathway that allows for exchange of CSF and interstitial fluid (ISF) consisting of three components: a para arterial CSF influx route; a paravenous ISF clearance route and a trans-parenchymal component that is dependent on astroglial water transport via aquaporin-4 (AQP4).
TE D
The authors of the recent studies used in vivo 2-photon and ex vivo confocal imaging of fluorescent CSF tracers and tracked movement of these tracers from subarachnoid space, into paravascular spaces through Virchow Robin space, along arterial vascular basement membrane and then to the brain capillary bed. They demonstrated CSF entering the interstitium at all levels of this pathway.
EP
Conversely, CSF tracer left the interstitium via large caliber draining veins. Fluorescent tracer introduced into the interstitium of the cortex, striatum or thalami was cleared medially into the internal cerebral veins. The authors also employed AQP4 knowckout mice and repeated the experiments showed that CSF influx into and through the experimental mice was significantly slower than wild type mice by at approximately 70%.
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Iliff et al. showed that the beta-amyloid clearance was facilitated by the aforementioned pathway, supporting the concept of this pathway as a lymphatic-analog for the brain. Moreover, in work by Xie et al., the same group showed marked 60% volume expansion of the interstitial space during sleep or anesthesia [Xie 2013]. Thus, the “pump” mechanism of volume expansion and subsequent contraction may be an important factor in brain homeostasis and a teleological reason for sleep. Other possible interactions
Iliff and Nedergaard summarize their present thoughts in an article in Stroke 2013 noting that astrogliosis is a final common pathway of many mechanistically distinct forms of neurological injury such as trauma, hemorrhage and ischemia. In their work, the AQP4 expression in injured brain is chaotic in contrast to the normal state of AQP4 activity preponderance in the perivascular spaces which may impede clearance of interstitial waste, not limited to beta amyloid or other aggregates seen in neurodegenerative diseases.
ACCEPTED MANUSCRIPT
Their work also raises the possibility of venous hypertension’s effect in CSF dysregulation, as their work has shown that a good portion of CSF clearance is mediated through the “glymphatic system” into the intracranial venous network.
The implications of a glympathic system may well surprise us.
SC
RI PT
Gaberel et al. report CSF injection of gadolinium chelate after ischemic stroke and subarachnoid hemorrhage and demonstrated impaired glymphatic perfusion and clearance using an magnetic resonance imaging method to assess movement of gadolinium in the CSF – they also showed improvement in glymphatic perfusion after intraventricular injection of tissue type plasminogen activator. Another thought occurs - if sleep is important to normal interstitial homeostasis, it draws attention to management of the neurocritically ill – if blood is to be cleared through the glymphatic system in subarachnoid hemorrhage, shouldn’t patients be allowed to sleep more?
M AN U
Schwalbe G: Die Arachnoidalraum ein Lymphraum und sein Zusammenhang mit den Perichorioidalraum. Zbl med Wiss Zentralblatt fur die medizinischen Wissenschaften 1869, 7:465-467. Abbott NJ. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int. 2004;45:545–552. Aukland K, Reed RK. Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev. 1993;73:1–78.
TE D
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Science translational medicine. 2012;4:147ra111 Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013;123:1299–1309.
EP
Koh L, Zakharov A, Johnston M. Integration of the subarachnoid space and lymphatics: is it time to embrace a new concept of cerebrospinal fluid absorption? Cerebrospinal Fluid Res. 2005;2:6.
AC C
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., ... & Nedergaard, M. (2013). Sleep drives metabolite clearance from the adult brain.Science, 342(6156), 373-377. Iliff, J. J., & Nedergaard, M. (2013). Is there a cerebral lymphatic system?.Stroke, 44(6 suppl 1), S93-S95. Gaberel, T., Gakuba, C., Goulay, R., De Lizarrondo, S. M., Hanouz, J. L., Emery, E., ... & Gauberti, M. (2014). Impaired Glymphatic Perfusion After Strokes Revealed by Contrast-Enhanced MRI A New Target for Fibrinolysis?.Stroke, 45(10), 3092-3096.
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Figure 1.
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ACCEPTED MANUSCRIPT
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Schematic of glymphatic pathway function in healthy and diseased brain. A, healthy brain; cerebrospinal fluid (CSF) from the subarachnoid space enters the brain, along para-arterial channels then entering the interstitial space, exchanging with interstitial fluid (ISF), clearing to paravenous spaces along large draining veins. Convective bulk fluid between para-arterial CSF influx and para-venous ISF efflux is facilitated by polarized aquaporin-4 expressed along perivascular astrocytic endfeet. B, astrogliotic brain causes mislocation of the aquaporin 4 away from the endfeet and is now distributed throughout the parenchyma and interstitium with resulting accumulation of undesirable metabolites. Reprinted with permission from Stroke.
S1878-8750(15)00195-3
DOI:
10.1016/j.wneu.2015.03.001
Reference:
WNEU 2752
To appear in:
World Neurosurgery
Please cite this article as: Hui FK, News Report: Clearing your mind: A Glymphatic System?, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.03.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
News Report Clearing your mind: A Glymphatic System?
SC
RI PT
The ubiquitous lymphatic system serves to move interstitial fluids back into the vascular system clearing extracellular proteins and excess fluid – ubiquitous except for one organ system: the brain. Schwalbe et al. [Schwalbe 1869] were the first to demonstrate a connection between the subarachnoid space and the lymphatic system in dogs and rabbits, however the precise route has been difficult to ascertain. Koh et al. demonstrated fluorescein tracer in olfactory and respiratory epithelium within 10 minutes of injection of the cisterna magna and proposed that one of the primary clearance mechanisms for cerebrospinal fluid (CSF) clearance is through the cribriform plate [Koh 2005]. Other recent work has similiarly postulated various mechanisms for CSF and lymphatic connection [Auckland, Abbott]
M AN U
However, more recent work [Iliff 2012, Iliff 2013] has defined a brain wide anatomic pathway that allows for exchange of CSF and interstitial fluid (ISF) consisting of three components: a para arterial CSF influx route; a paravenous ISF clearance route and a trans-parenchymal component that is dependent on astroglial water transport via aquaporin-4 (AQP4).
TE D
The authors of the recent studies used in vivo 2-photon and ex vivo confocal imaging of fluorescent CSF tracers and tracked movement of these tracers from subarachnoid space, into paravascular spaces through Virchow Robin space, along arterial vascular basement membrane and then to the brain capillary bed. They demonstrated CSF entering the interstitium at all levels of this pathway.
EP
Conversely, CSF tracer left the interstitium via large caliber draining veins. Fluorescent tracer introduced into the interstitium of the cortex, striatum or thalami was cleared medially into the internal cerebral veins. The authors also employed AQP4 knowckout mice and repeated the experiments showed that CSF influx into and through the experimental mice was significantly slower than wild type mice by at approximately 70%.
AC C
Iliff et al. showed that the beta-amyloid clearance was facilitated by the aforementioned pathway, supporting the concept of this pathway as a lymphatic-analog for the brain. Moreover, in work by Xie et al., the same group showed marked 60% volume expansion of the interstitial space during sleep or anesthesia [Xie 2013]. Thus, the “pump” mechanism of volume expansion and subsequent contraction may be an important factor in brain homeostasis and a teleological reason for sleep. Other possible interactions
Iliff and Nedergaard summarize their present thoughts in an article in Stroke 2013 noting that astrogliosis is a final common pathway of many mechanistically distinct forms of neurological injury such as trauma, hemorrhage and ischemia. In their work, the AQP4 expression in injured brain is chaotic in contrast to the normal state of AQP4 activity preponderance in the perivascular spaces which may impede clearance of interstitial waste, not limited to beta amyloid or other aggregates seen in neurodegenerative diseases.
ACCEPTED MANUSCRIPT
Their work also raises the possibility of venous hypertension’s effect in CSF dysregulation, as their work has shown that a good portion of CSF clearance is mediated through the “glymphatic system” into the intracranial venous network.
The implications of a glympathic system may well surprise us.
SC
RI PT
Gaberel et al. report CSF injection of gadolinium chelate after ischemic stroke and subarachnoid hemorrhage and demonstrated impaired glymphatic perfusion and clearance using an magnetic resonance imaging method to assess movement of gadolinium in the CSF – they also showed improvement in glymphatic perfusion after intraventricular injection of tissue type plasminogen activator. Another thought occurs - if sleep is important to normal interstitial homeostasis, it draws attention to management of the neurocritically ill – if blood is to be cleared through the glymphatic system in subarachnoid hemorrhage, shouldn’t patients be allowed to sleep more?
M AN U
Schwalbe G: Die Arachnoidalraum ein Lymphraum und sein Zusammenhang mit den Perichorioidalraum. Zbl med Wiss Zentralblatt fur die medizinischen Wissenschaften 1869, 7:465-467. Abbott NJ. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int. 2004;45:545–552. Aukland K, Reed RK. Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev. 1993;73:1–78.
TE D
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Science translational medicine. 2012;4:147ra111 Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013;123:1299–1309.
EP
Koh L, Zakharov A, Johnston M. Integration of the subarachnoid space and lymphatics: is it time to embrace a new concept of cerebrospinal fluid absorption? Cerebrospinal Fluid Res. 2005;2:6.
AC C
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., ... & Nedergaard, M. (2013). Sleep drives metabolite clearance from the adult brain.Science, 342(6156), 373-377. Iliff, J. J., & Nedergaard, M. (2013). Is there a cerebral lymphatic system?.Stroke, 44(6 suppl 1), S93-S95. Gaberel, T., Gakuba, C., Goulay, R., De Lizarrondo, S. M., Hanouz, J. L., Emery, E., ... & Gauberti, M. (2014). Impaired Glymphatic Perfusion After Strokes Revealed by Contrast-Enhanced MRI A New Target for Fibrinolysis?.Stroke, 45(10), 3092-3096.
EP
Figure 1.
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
Schematic of glymphatic pathway function in healthy and diseased brain. A, healthy brain; cerebrospinal fluid (CSF) from the subarachnoid space enters the brain, along para-arterial channels then entering the interstitial space, exchanging with interstitial fluid (ISF), clearing to paravenous spaces along large draining veins. Convective bulk fluid between para-arterial CSF influx and para-venous ISF efflux is facilitated by polarized aquaporin-4 expressed along perivascular astrocytic endfeet. B, astrogliotic brain causes mislocation of the aquaporin 4 away from the endfeet and is now distributed throughout the parenchyma and interstitium with resulting accumulation of undesirable metabolites. Reprinted with permission from Stroke.