AUTHOR=Mosso Jessie , Briand Guillaume , Pierzchala Katarzyna , Simicic Dunja , Sierra Alejandra , Abdollahzadeh Ali , Jelescu Ileana O. , Cudalbu Cristina 

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

JOURNAL=Frontiers in Neuroscience

VOLUME=18

YEAR=2024

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1344076

DOI=10.3389/fnins.2024.1344076

ISSN=1662-453X

ABSTRACT=<sec id="sec1"><title>Introduction</title><p>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 <sup>1</sup>H 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 <italic>ex vivo</italic> 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 <italic>in vivo</italic> by monitoring the diffusion properties of the major brain metabolites.</p></sec><sec id="sec2"><title>Methods</title><p>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. <sup>1</sup>H-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 <italic>b</italic>-value = 25 ms/μm<sup>2</sup>) on a 9.4 T scanner. The <italic>in vivo</italic> MRS acquisitions were further validated with histological measures (immunohistochemistry, Golgi-Cox, electron microscopy).</p></sec><sec id="sec3"><title>Results</title><p>The characteristic <sup>1</sup>H-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.</p></sec><sec id="sec4"><title>Discussion</title><p>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 <italic>ex vivo</italic> by histology. These findings give new insights into metabolic and microstructural abnormalities associated with high brain glutamine and its consequences in type C HE.</p></sec>