Biomarkers of Traumatic Injury Are Transported from Brain to Blood Via the Glymphatic System

Overview

Journal J Neurosci

Specialty Neurology

Date 2015 Jan 16

PMID 25589747

Citations 251

Authors

Benjamin A Plog

Matthew L Dashnaw

Emi Hitomi

Weiguo Peng

Yonghong Liao

Nanhong Lou

Rashid Deane

Maiken Nedergaard

Affiliations

Soon will be listed here.

Abstract

The nonspecific and variable presentation of traumatic brain injury (TBI) has motivated an intense search for blood-based biomarkers that can objectively predict the severity of injury. However, it is not known how cytosolic proteins released from traumatized brain tissue reach the peripheral blood. Here we show in a murine TBI model that CSF movement through the recently characterized glymphatic pathway transports biomarkers to blood via the cervical lymphatics. Clinically relevant manipulation of glymphatic activity, including sleep deprivation and cisternotomy, suppressed or eliminated TBI-induced increases in serum S100β, GFAP, and neuron specific enolase. We conclude that routine TBI patient management may limit the clinical utility of blood-based biomarkers because their brain-to-blood transport depends on glymphatic activity.

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References

Papadopoulos M, Manley G, Krishna S, Verkman A . Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J. 2004; 18(11):1291-3. DOI: 10.1096/fj.04-1723fje. View

Papa L, Ramia M, Kelly J, Burks S, Pawlowicz A, Berger R . Systematic review of clinical research on biomarkers for pediatric traumatic brain injury. J Neurotrauma. 2012; 30(5):324-38. PMC: 8881956. DOI: 10.1089/neu.2012.2545. View

Simard J, Woo S, Schwartzbauer G, Gerzanich V . Sulfonylurea receptor 1 in central nervous system injury: a focused review. J Cereb Blood Flow Metab. 2012; 32(9):1699-717. PMC: 3434627. DOI: 10.1038/jcbfm.2012.91. View

Liang D, Bhatta S, Gerzanich V, Simard J . Cytotoxic edema: mechanisms of pathological cell swelling. Neurosurg Focus. 2007; 22(5):E2. PMC: 2740913. DOI: 10.3171/foc.2007.22.5.3. View

Papadopoulos M, Verkman A . Aquaporin-4 gene disruption in mice reduces brain swelling and mortality in pneumococcal meningitis. J Biol Chem. 2005; 280(14):13906-12. DOI: 10.1074/jbc.M413627200. View

Stone J, Childs S, Smith L, Battin M, Papadakos P, Huang J . Hourly neurologic assessments for traumatic brain injury in the ICU. Neurol Res. 2014; 36(2):164-9. DOI: 10.1179/1743132813Y.0000000285. View

Ren Z, Iliff J, Yang L, Yang J, Chen X, Chen M . 'Hit & Run' model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation. J Cereb Blood Flow Metab. 2013; 33(6):834-45. PMC: 3677112. DOI: 10.1038/jcbfm.2013.30. View

Mannix R, Meehan W, Mandeville J, Grant P, Gray T, Berglass J . Clinical correlates in an experimental model of repetitive mild brain injury. Ann Neurol. 2013; 74(1):65-75. PMC: 6312716. DOI: 10.1002/ana.23858. View

Darwish H, Dawish H, Mahmood A, Schallert T, Chopp M, Therrien B . Mild traumatic brain injury (MTBI) leads to spatial learning deficits. Brain Inj. 2012; 26(2):151-65. PMC: 3925503. DOI: 10.3109/02699052.2011.635362. View

10.

Ulrich J, Burchett J, Restivo J, Schuler D, Verghese P, Mahan T . In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol Neurodegener. 2013; 8:13. PMC: 3640999. DOI: 10.1186/1750-1326-8-13. View

11.

Zetterberg H, Smith D, Blennow K . Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood. Nat Rev Neurol. 2013; 9(4):201-10. PMC: 4513656. DOI: 10.1038/nrneurol.2013.9. View

12.

Johnston M, Zakharov A, Papaiconomou C, Salmasi G, Armstrong D . Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species. Cerebrospinal Fluid Res. 2005; 1(1):2. PMC: 546409. DOI: 10.1186/1743-8454-1-2. View

13.

Simard M, Nedergaard M . The neurobiology of glia in the context of water and ion homeostasis. Neuroscience. 2004; 129(4):877-96. DOI: 10.1016/j.neuroscience.2004.09.053. View

14.

Takeda S, Sato N, Ikimura K, Nishino H, Rakugi H, Morishita R . Novel microdialysis method to assess neuropeptides and large molecules in free-moving mouse. Neuroscience. 2011; 186:110-9. DOI: 10.1016/j.neuroscience.2011.04.035. View

15.

Yamada K, Cirrito J, Stewart F, Jiang H, Finn M, Holmes B . In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci. 2011; 31(37):13110-7. PMC: 4299126. DOI: 10.1523/JNEUROSCI.2569-11.2011. View

16.

Bratton S, Chestnut R, Ghajar J, McConnell Hammond F, Harris O, Hartl R . Guidelines for the management of severe traumatic brain injury. VI. Indications for intracranial pressure monitoring. J Neurotrauma. 2007; 24 Suppl 1:S37-44. DOI: 10.1089/neu.2007.9990. View

17.

Iliff J, Wang M, Zeppenfeld D, Venkataraman A, Plog B, Liao Y . Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci. 2013; 33(46):18190-9. PMC: 3866416. DOI: 10.1523/JNEUROSCI.1592-13.2013. View

18.

Papadopoulos M, Verkman A . Aquaporin-4 and brain edema. Pediatr Nephrol. 2007; 22(6):778-84. PMC: 6904420. DOI: 10.1007/s00467-006-0411-0. View

19.

Haj-Yasein N, Vindedal G, Eilert-Olsen M, Gundersen G, Skare O, Laake P . Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet. Proc Natl Acad Sci U S A. 2011; 108(43):17815-20. PMC: 3203818. DOI: 10.1073/pnas.1110655108. View

20.

Boulton M, Young A, Hay J, Armstrong D, Flessner M, Schwartz M . Drainage of CSF through lymphatic pathways and arachnoid villi in sheep: measurement of 125I-albumin clearance. Neuropathol Appl Neurobiol. 1996; 22(4):325-33. DOI: 10.1111/j.1365-2990.1996.tb01111.x. View