@article{8f5883476a374191a689dba8d31f1a6d,
title = "Impaired brain glymphatic flow in experimental hepatic encephalopathy",
abstract = "Background & Aims: Neuronal function is exquisitely sensitive to alterations in the extracellular environment. In patients with hepatic encephalopathy (HE), accumulation of metabolic waste products and noxious substances in the interstitial fluid of the brain is thought to result from liver disease and may contribute to neuronal dysfunction and cognitive impairment. This study was designed to test the hypothesis that the accumulation of these substances, such as bile acids, may result from reduced clearance from the brain. Methods: In a rat model of chronic liver disease with minimal HE (the bile duct ligation [BDL] model), we used emerging dynamic contrast-enhanced MRI and mass-spectroscopy techniques to assess the efficacy of the glymphatic system, which facilitates clearance of solutes from the brain. Immunofluorescence of aquaporin-4 (AQP4) and behavioural experiments were also performed. Results: We identified discrete brain regions (olfactory bulb, prefrontal cortex and hippocampus) of altered glymphatic clearance in BDL rats, which aligned with cognitive/behavioural deficits. Reduced AQP4 expression was observed in the olfactory bulb and prefrontal cortex in HE, which could contribute to the pathophysiological mechanisms underlying the impairment in glymphatic function in BDL rats. Conclusions: This study provides the first experimental evidence of impaired glymphatic flow in HE, potentially mediated by decreased AQP4 expression in the affected regions. Lay summary: The 'glymphatic system' is a newly discovered brain-wide pathway that facilitates clearance of various sub-stances that accumulate in the brain due to its activity. This study evaluated whether the function of this system is altered in a model of brain dysfunction that occurs in cirrhosis. For the first time, we identified that the clearance of substances from the brain in cirrhosis is reduced because this clearance system is defective. This study proposes a new mechanism of brain dysfunction in patients with cirrhosis and provides new targets for therapy. (C) 2018 European Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND license.",
keywords = "AMMONIA, ANESTHESIA, CEREBROSPINAL-FLUID, Cirrhosis, Glymphatic system, Hepatic encephalopathy, MRI, Mass spectrometry, PATHWAY, RAT-BRAIN, SYSTEM, TRANSPORT",
author = "Anna Hadjihambi and Harrison, {Ian F.} and Marta Costas-Rodriguez and Frank Vanhaecke and Natalia Arias and Rocio Gallego-Duran and Svetlana Mastitskaya and Hosford, {Patrick S.} and Damink, {Steven W. M. Olde} and Nathan Davies and Abeba Habtesion and Lythgoe, {Mark F.} and Gourine, {Alexander V.} and Rajiv Jalan",
note = "Funding Information: This study was supported by Grand Challenges UCL and The Wellcome Trust (to Alexander V. Gourine). Alexander V. Gourine is a Wellcome Trust Senior Research Fellow (Refs: 095064 and 200893). Mark F. Lythgoe receives funding from the EPSRC (EP/N034864/1); the King{\textquoteright}s College London and UCL Comprehensive Cancer Imaging Centre CR-UK & EPSRC, in association with the MRC and DoH (England); UK Regenerative Medicine Platform Safety Hub (MRC: MR/K026739/1); Eli Lilly and Company. Authors would like to thank, Ozama Ismail for his help with the surgical preparation associated with the dynamic contrast-enhanced MRI, Dr. Jack Wells for his assistance in setting up the MRI protocol and Christina Elia for her help with figures. Publisher Copyright: {\textcopyright} 2018 European Association for the Study of the Liver",
year = "2019",
month = jan,
doi = "10.1016/j.jhep.2018.08.021",
language = "English",
volume = "70",
pages = "40--49",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier Science",
number = "1",
}