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Impaired brain glymphatic flow in experimental hepatic encephalopathy

(2019) JOURNAL OF HEPATOLOGY. 70(1). p.40-49
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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.
Keywords
Hepatic encephalopathy, Glymphatic system, MRI, Cirrhosis, Mass spectrometry, CEREBROSPINAL-FLUID, RAT-BRAIN, SYSTEM, PATHWAY, AMMONIA, ANESTHESIA, TRANSPORT, MRI

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Citation

Please use this url to cite or link to this publication:

Chicago
Hadjihambi, Anna, Ian F Harrison, Marta Costas Rodriguez, Frank Vanhaecke, Natalia Arias, Rocío Gallego-Durán, Svetlana Mastitskaya, et al. 2019. “Impaired Brain Glymphatic Flow in Experimental Hepatic Encephalopathy.” Journal of Hepatology 70 (1): 40–49.
APA
Hadjihambi, A., Harrison, I. F., Costas Rodriguez, M., Vanhaecke, F., Arias, N., Gallego-Durán, R., Mastitskaya, S., et al. (2019). Impaired brain glymphatic flow in experimental hepatic encephalopathy. JOURNAL OF HEPATOLOGY, 70(1), 40–49.
Vancouver
1.
Hadjihambi A, Harrison IF, Costas Rodriguez M, Vanhaecke F, Arias N, Gallego-Durán R, et al. Impaired brain glymphatic flow in experimental hepatic encephalopathy. JOURNAL OF HEPATOLOGY. 2019;70(1):40–9.
MLA
Hadjihambi, Anna et al. “Impaired Brain Glymphatic Flow in Experimental Hepatic Encephalopathy.” JOURNAL OF HEPATOLOGY 70.1 (2019): 40–49. Print.
@article{8586870,
  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. },
  author       = {Hadjihambi, Anna and Harrison, Ian F and Costas Rodriguez, Marta and Vanhaecke, Frank and Arias, Natalia and Gallego-Dur{\'a}n, Roc{\'i}o and Mastitskaya, Svetlana and Hosford, Patrick S and Olde Damink, Steven WM and Davies, Nathan and Habtesion, Abeba and Lythgoe, Mark F and Gourine, Alexander V and Jalan, Rajiv},
  issn         = {0168-8278},
  journal      = {JOURNAL OF HEPATOLOGY},
  language     = {eng},
  number       = {1},
  pages        = {40--49},
  title        = {Impaired brain glymphatic flow in experimental hepatic encephalopathy},
  url          = {http://dx.doi.org/10.1016/j.jhep.2018.08.021},
  volume       = {70},
  year         = {2019},
}

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