Abstract
Neuronal function is exquisitely sensitive to alterations in extracellular environment. In patients with hepatic encephalopathy (HE), accumulation of metabolic waste products and noxious substances in the interstitial fluid of the brain may contribute to neuronal dysfunction and cognitive impairment. In a rat model of chronic liver disease, we used an emerging dynamic contrast-enhanced MRI technique to assess the efficacy of the glymphatic system, which facilitates clearance of solutes from the brain. We identified discrete brain regions (olfactory bulb, prefrontal cortex and hippocampus) of altered glymphatic flow, which aligned with cognitive/behavioural deficits. Although the underlying pathophysiological mechanisms remain unclear, this study provides the first experimental evidence of impaired glymphatic clearance in HE.
Footnotes
↵∗ Joint first authors: A.H and I.H are joint first authors
↵∗∗ Joint senior authors: A.V.G. and R.J. are joint last authors.
Contact information: Rajiv Jalan, Professor of Hepatology, Liver Failure Group ILDH, Division of Medicine, UCL Medical School, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK. Phone: +442074332795 r.jalan{at}ucl.ac.uk; or, Alexander V. Gourine, Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK. a.gourine{at}ucl.ac.uk
Conflict of interest statement:, Anna Hadjihambi: N/A, Ian F. Harrison: N/A, Natalia Arias: N/A, Rocío Gallego-Durán: N/A, Patrick Hosford: N/A, Nathan Davies: N/A, Abeba Habtesion: N/A, Mark F. Lythgoe: N/A, Alexander V. Gourine: N/A, Rajiv Jalan: Rajiv Jalan has research collaborations with Ocera and Takeda and consults with Ocera and has received speaking fees from Norgine. Rajiv Jalan is the inventor of OCR-002, which has been patented by UCL and licensed to Ocera Therapeutics. He is also the founder of Yaqrit limited, a spin out company from University College London.
- Abbreviations
- HE
- Hepatic encephalopathy
- CSF
- Cerebrospinal fluid
- ISF
- Interstitial fluid
- BDL
- Bile duct ligation
- CLD
- Chronic liver disease
- mHE
- Minimal HE
- Gd-DTPA
- Gadolinium
- ICP
- Intracranial pressure
- ROI
- Region of interest
- SEM
- Standard error mean
