Diffusion of brain metabolites highlights altered brain microstructure in type C hepatic encephalopathy: a 9.4 T preliminary study

Jessie Mosso; Guillaume Briand; Katarzyna Pierzchala; Dunja Simicic; Alejandra Sierra; Ali Abdollahzadeh; Ileana O Jelescu; Cristina Cudalbu

doi:10.3389/fnins.2024.1344076

Diffusion of brain metabolites highlights altered brain microstructure in type C hepatic encephalopathy: a 9.4 T preliminary study

Front Neurosci. 2024 Mar 20:18:1344076. doi: 10.3389/fnins.2024.1344076. eCollection 2024.

Authors

Jessie Mosso^#^{1

2}, Guillaume Briand^#^{1

2}, Katarzyna Pierzchala^{1

2}, Dunja Simicic^{1

2}, Alejandra Sierra³, Ali Abdollahzadeh⁴, Ileana O Jelescu^{5

6}, Cristina Cudalbu^{1

2}

Affiliations

¹ CIBM Center for Biomedical Imaging, Lausanne, Switzerland.
² Animal Imaging and Technology, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland.
³ A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
⁴ Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States.
⁵ Department of Radiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
⁶ Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.

^# Contributed equally.

Abstract

Introduction: Type C hepatic encephalopathy (HE) is a decompensating event of chronic liver disease leading to severe motor and cognitive impairment. The progression of type C HE is associated with changes in brain metabolite concentrations measured by ¹H magnetic resonance spectroscopy (MRS), most noticeably a strong increase in glutamine to detoxify brain ammonia. In addition, alterations of brain cellular architecture have been measured ex vivo by histology in a rat model of type C HE. The aim of this study was to assess the potential of diffusion-weighted MRS (dMRS) for probing these cellular shape alterations in vivo by monitoring the diffusion properties of the major brain metabolites.

Methods: The bile duct-ligated (BDL) rat model of type C HE was used. Five animals were scanned before surgery and 6- to 7-week post-BDL surgery, with each animal being used as its own control. ¹H-MRS was performed in the hippocampus (SPECIAL, TE = 2.8 ms) and dMRS in a voxel encompassing the entire brain (DW-STEAM, TE = 15 ms, diffusion time = 120 ms, maximum b-value = 25 ms/μm²) on a 9.4 T scanner. The in vivo MRS acquisitions were further validated with histological measures (immunohistochemistry, Golgi-Cox, electron microscopy).

Results: The characteristic ¹H-MRS pattern of type C HE, i.e., a gradual increase of brain glutamine and a decrease of the main organic osmolytes, was observed in the hippocampus of BDL rats. Overall increased metabolite diffusivities (apparent diffusion coefficient and intra-stick diffusivity-Callaghan's model, significant for glutamine, myo-inositol, and taurine) and decreased kurtosis coefficients were observed in BDL rats compared to control, highlighting the presence of osmotic stress and possibly of astrocytic and neuronal alterations. These results were consistent with the microstructure depicted by histology and represented by a decline in dendritic spines density in neurons, a shortening and decreased number of astrocytic processes, and extracellular edema.

Discussion: dMRS enables non-invasive and longitudinal monitoring of the diffusion behavior of brain metabolites, reflecting in the present study the globally altered brain microstructure in BDL rats, as confirmed ex vivo by histology. These findings give new insights into metabolic and microstructural abnormalities associated with high brain glutamine and its consequences in type C HE.

Keywords: bile duct ligation; brain metabolism; diffusion-weighted magnetic resonance spectroscopy; hepatic encephalopathy; in vivo magnetic resonance spectroscopy; rat brain; ultra high magnetic field.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. CC, KP, and JM were supported by the CIBM Center for Biomedical Imaging of the UNIL, UNIGE, HUG, CHUV, EPFL, the Leenaards and Jeantet Foundations, and the SNSF project no. 310030_201218. IJ was supported by SNSF grant PCEFP2_194260. AS was supported by the Academy of Finland Research Project (#323385).