Glymphatic flow impairment

Cerebrospinal fluid circulation failure in the pathogenesis of post-craniectomy glymphatic flow impairment ¹⁾.

Cranial neurosurgical procedures can cause changes in brain function. There are many potential explanations, but the effect of simply opening the skull has not been addressed, except for research into syndrome of the trephined. The glymphatic circulation, by which CSF and interstitial fluid circulate through periarterial spaces, brain parenchyma, and perivenous spaces, depends on arterial pulsations to provide the driving force for bulk flow; opening the cranial cavity could dampen this force.

Plog et al., hypothesized that a craniectomy, without any other pathological insult, is sufficient to alter brain function due to reduced arterial pulsatility and decreased glymphatic flow. Furthermore, they postulated that glymphatic impairment would produce activation of astrocytes and microglia; with the reestablishment of a closed cranial compartment, the glymphatic impairment, astrocytic/microglial activation, and neurobehavioral decline caused by opening the cranial compartment might be reversed.

Using two-photon in vivo microscopy, the pulsatility index of cortical vessels was quantified through a thinned murine skull and then again after craniectomy. Glymphatic influx was determined with ex vivo fluorescence microscopy of mice 0, 14, 28, and 56 days following craniectomy or cranioplasty; brain sections were immunohistochemically labeled for GFAP and CD68. Motor and cognitive performance was quantified with rotarod and novel object recognition tests at baseline and 14, 21, and 28 days following craniectomy or cranioplasty.

Penetrating arterial pulsatility decreased significantly and bilaterally following unilateral craniectomy, producing immediate and chronic impairment of glymphatic CSF influx in the ipsilateral and contralateral brain parenchyma. Craniectomy-related glymphatic dysfunction was associated with an astrocytic and microglial inflammatory response, as well as with the development of motor and cognitive deficits. Recovery of glymphatic flow preceded reduced gliosis and return of normal neurological function, and cranioplasty accelerated this recovery.

Craniectomy causes glymphatic dysfunction, gliosis, and changes in neurological function in this murine model of syndrome of the trephined ²⁾.

1: Gallina P, Scollato A, Nicoletti C, Lolli F. Letter to the Editor. Cerebrospinal fluid circulation failure in the pathogenesis of post-craniectomy glymphatic flow impairment. J Neurosurg. 2019 Nov 29:1-4. doi: 10.3171/2019.6.JNS191758. [Epub ahead of print] PubMed PMID: 31783370.

2: Plog BA, Lou N, Pierre CA, Cove A, Kenney HM, Hitomi E, Kang H, Iliff JJ, Zeppenfeld DM, Nedergaard M, Vates GE. When the air hits your brain: decreased arterial pulsatility after craniectomy leading to impaired glymphatic flow. J Neurosurg. 2019 May 17:1-14. doi: 10.3171/2019.2.JNS182675. [Epub ahead of print] PubMed PMID: 31100725.

3: Rajna Z, Raitamaa L, Tuovinen T, Heikkila J, Kiviniemi V, Seppanen T. 3D Multi-Resolution Optical Flow Analysis of Cardiovascular Pulse Propagation in Human Brain. IEEE Trans Med Imaging. 2019 Sep;38(9):2028-2036. doi: 10.1109/TMI.2019.2904762. Epub 2019 Mar 15. PubMed PMID: 30892202.

4: Schubert JJ, Veronese M, Marchitelli L, Bodini B, Tonietto M, Stankoff B, Brooks DJ, Bertoldo A, Edison P, Turkheimer FE. Dynamic (11)C-PiB PET Shows Cerebrospinal Fluid Flow Alterations in Alzheimer Disease and Multiple Sclerosis. J Nucl Med. 2019 Oct;60(10):1452-1460. doi: 10.2967/jnumed.118.223834. Epub 2019 Mar 8. PubMed PMID: 30850505; PubMed Central PMCID: PMC6785797.

5: Yu P, Venkat P, Chopp M, Zacharek A, Shen Y, Ning R, Liang L, Li W, Zhang L, Landschoot-Ward J, Jiang R, Chen J. Role of microRNA-126 in vascular cognitive impairment in mice. J Cereb Blood Flow Metab. 2018 Sep 14:271678×18800593. doi: 10.1177/0271678×18800593. [Epub ahead of print] PubMed PMID: 30215264.

6: Hadjihambi A, Harrison IF, Costas-Rodríguez M, Vanhaecke F, Arias N, Gallego-Durán R, Mastitskaya S, Hosford PS, Olde Damink SWM, Davies N, Habtesion A, Lythgoe MF, Gourine AV, Jalan R. Impaired brain glymphatic flow in experimental hepatic encephalopathy. J Hepatol. 2019 Jan;70(1):40-49. doi: 10.1016/j.jhep.2018.08.021. Epub 2018 Sep 8. Erratum in: J Hepatol. 2019 Mar;70(3):582. PubMed PMID: 30201461.

7: Sun BL, Wang LH, Yang T, Sun JY, Mao LL, Yang MF, Yuan H, Colvin RA, Yang XY. Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases. Prog Neurobiol. 2018 Apr - May;163-164:118-143. doi: 10.1016/j.pneurobio.2017.08.007. Epub 2017 Sep 10. Review. PubMed PMID: 28903061.

8: Schain AJ, Melo-Carrillo A, Strassman AM, Burstein R. Cortical Spreading Depression Closes Paravascular Space and Impairs Glymphatic Flow: Implications for Migraine Headache. J Neurosci. 2017 Mar 15;37(11):2904-2915. doi: 10.1523/JNEUROSCI.3390-16.2017. Epub 2017 Feb 13. PubMed PMID: 28193695; PubMed Central PMCID: PMC5354333.

9: Pistollato F, Sumalla Cano S, Elio I, Masias Vergara M, Giampieri F, Battino M. Associations between Sleep, Cortisol Regulation, and Diet: Possible Implications for the Risk of Alzheimer Disease. Adv Nutr. 2016 Jul 15;7(4):679-89. doi: 10.3945/an.115.011775. Print 2016 Jul. Review. PubMed PMID: 27422503; PubMed Central PMCID: PMC4942871.

10: Jiang Q, Zhang L, Ding G, Davoodi-Bojd E, Li Q, Li L, Sadry N, Nedergaard M, Chopp M, Zhang Z. Impairment of the glymphatic system after diabetes. J Cereb Blood Flow Metab. 2017 Apr;37(4):1326-1337. doi: 10.1177/0271678×16654702. Epub 2016 Jan 1. PubMed PMID: 27306755; PubMed Central PMCID: PMC5453454.

11: Rivera-Rivera LA, Turski P, Johnson KM, Hoffman C, Berman SE, Kilgas P, Rowley HA, Carlsson CM, Johnson SC, Wieben O. 4D flow MRI for intracranial hemodynamics assessment in Alzheimer's disease. J Cereb Blood Flow Metab. 2016 Oct;36(10):1718-1730. Epub 2015 Nov 25. PubMed PMID: 26661239; PubMed Central PMCID: PMC5076787.

12: Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Xie L, Kang H, Xu Q, Liew JA, Plog BA, Ding F, Deane R, Nedergaard M. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol. 2014 Dec;76(6):845-61. doi: 10.1002/ana.24271. Epub 2014 Sep 26. PubMed PMID: 25204284; PubMed Central PMCID: PMC4245362.