IntroductionType 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.MethodsThe 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).ResultsThe 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.DiscussiondMRS 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.

中文翻译：

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脑代谢物的扩散凸显了 C 型肝性脑病中脑微结构的改变：一项 9.4 T 初步研究

简介 C 型肝性脑病 (HE) 是一种慢性肝病失代偿事件，可导致严重的运动和认知障碍。 C 型 HE 的进展与通过测量脑代谢物浓度的变化相关1H 磁共振波谱 (MRS)，最明显的是谷氨酰胺的强烈增加，以解毒脑氨。此外，还测量了脑细胞结构的改变离体通过在 C 型 HE 大鼠模型中进行组织学检查。本研究的目的是评估弥散加权 MRS (dMRS) 探测这些细胞形状变化的潜力体内通过监测脑内主要代谢物的扩散特性。方法采用C型HE胆管结扎(BDL)大鼠模型。在手术前和 BDL 手术后 6 至 7 周对五只动物进行扫描，每只动物用作自己的对照。1H-MRS 在海马体中进行（特殊，TE = 2.8 ms），dMRS 在包含整个大脑的体素中进行（DW-STEAM，TE = 15 ms，扩散时间 = 120 ms，最大乙-值 = 25 ms/μm2）在 9.4 T 扫描仪上。这体内通过组织学测量（免疫组织化学、高尔基-考克斯、电子显微镜）进一步验证 MRS 采集结果。结果特征1在 BDL 大鼠的海马中观察到 C 型 HE 的 H-MRS 模式，即脑谷氨酰胺逐渐增加，主要有机渗透压物质逐渐减少。与对照组相比，在 BDL 大鼠中观察到总体代谢物扩散性增加（表观扩散系数和棒内扩散性 - 卡拉汉模型，对谷氨酰胺、肌醇和牛磺酸显着）和峰度系数降低，突出了渗透压的存在，并且可能存在星形细胞和神经元改变。这些结果与组织学描绘的微观结构一致，表现为神经元树突棘密度下降、星形胶质细胞过程缩短和数量减少以及细胞外水肿。讨论dMRS 能够对脑代谢物的扩散行为进行非侵入性纵向监测，反映了本研究中 BDL 大鼠大脑微结构的整体改变，已证实离体通过组织学。这些发现为与高脑谷氨酰胺相关的代谢和微观结构异常及其在 C 型 HE 中的后果提供了新的见解。