PET and MR imaging of neuroinflammation in hepatic encephalopathy

Abstract

Neurological or psychiatric abnormalities associated with hepatic encephalopathy (HE) range from subclinical findings to coma. HE is commonly accompanied with the accumulation of toxic substances in bloodstream. The toxicity effect of hyperammonemia on astrocyte, such as the alteration in neurotransmission, oxidative stress, astrocyte swelling, is considered as an important factor in the pathogenesis of HE. Besides, neuroinflammation has captured more attention in the process of HE, but the mechanism of neuroinflammation leading to HE remains unclear. Molecular imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) targeting activated microglia and/ or other mediators appear to be promising noninvasive approaches to assess HE. This review focuses on novel imaging and therapy strategies of neuroinflammation in HE.

The Neurobiology of Hepatic Encephalopathy

“…In addition, studies have demonstrated that hyperammonemia is not a sufficient condition to produce cognitive deficits in minimal hepatic encephalopathy [11].…”

“…Circulating cytokines, such as tumor necrosis factor alpha (TNFα), interleukin 1b (IL-1b) and interleukin 6, induce the synthesis of nitric oxide and prostanoids in endothelial cells, triggering a state of inflammatory hyperemia that facilitates the uptake of ammonia by the central nervous system [9]. In addition, the proinflammatory cytokines generated by the vascular endothelium activate the cells of the immune system in the brain parenchyma and the microglia, contributing indirectly to neuroinflammation [11].…”

“…Secondly, exceeding glutamine is transported to the mitochondria, where, by glutaminase action, it is hydrolyzed back into glutamate and ammonia. The passage of the latter to the interior of the mitochondria causes oxidative stress and modifies the internal mitochondrial membrane diffusivity, through the opening of permeability transition pore, causing water accumulation in the mitochondrial matrix, low capacity of oxidative phosphorylation, and low adenosine triphosphate (ATP) production [11,12]. This results in a vicious cycle of formation of reactive oxygen and nitrogen species (free radicals) with mitochondrial damage [9].…”

“…Furthermore, due to the osmotic imbalance generated by the accumulation of glutamine and glutamate, astrocytes export choline and myo-inositol, its main osmolyte, to the extracellular space, which leads to a reduction in the levels of the later, in an attempt to counterbalance the intracellular edema. This mechanism is known as regulatory volume decrease [11,21,23]. The diffusion-weighted imaging, in turn, shows interstitial edema resulting from the exportation of osmolytes from the astrocytes into the extracellular space, both in the white and gray matters.…”

The brain following transjugular intrahepatic portosystemic shunt: the perspective from neuroimaging

“…In addition, PET with pharmacological ligands such as the translocator protein and other radioligands (eg. DPA-714 labeled with fluorine 18) (Su et al 2015) may be used to evaluate the role of neuroinflammation in the progression of post-TIPS HE by mapping the activated microglia in the brain. Finally, new multimodality neuromolecular imaging techniques such as hybrid PET/MR which can simultaneously provide molecular, physiological, structural and functional information in a single examination, may comprehensively uncover the pathogenesis of post-TIPS HE.…”