In vitro1 H MRS of human bile has shown potential in the diagnosis of various hepatopancreatobiliary (HPB) diseases. Previously, in vivo 1 H MRS of human bile in gallbladder using a 1.5 T scanner demonstrated the possibility of quantification of choline-containing phospholipids (chol-PLs). However, other lipid components such as bile acids play an important role in the pathophysiology of the HPB system. We have employed a higher magnetic field strength (3 T), and a custom-built receive array coil, to improve the quality of in vivo 1 H MRS of human bile in the gallbladder. We obtained significant improvement in the quality of 1D spectra (17 healthy volunteers) using a respiratory-gated PRESS sequence with well distinguished signals for total bile acids (TBAs) plus cholesterol resonating at 0.66 ppm, taurine-conjugated bile acids (TCBAs) at 3.08 ppm, chol-PLs at 3.22 ppm, glycineconjugated bile acids (GCBAs) at 3.74 ppm, and the amide proton (ÀNH) arising from GCBAs and TCBAs in the region 7.76-8.05 ppm. The peak areas of these signals were measured by deconvolution, and subsequently the molar concentrations of metabolites were estimated with good accuracy, except for that of TBAs plus cholesterol. The concentration of TBAs plus cholesterol was overestimated in some cases, which could be due to lipid contamination. In addition, we report the first 2D L-COSY spectra of human gallbladder bile in vivo (obtained in 15 healthy volunteers). 2D L-COSY spectra will be helpful in differentiating various biliary chol-PLs in pathological conditions of the HPB system.
Primary sclerosing cholangitis (PSC) has been considered to be either an "autoimmune disease" or a "bile acid-induced injury." In vitro MRS studies on PSC patients have limitations due to the contamination of bile with contrast agent (commonly administered during endoscopic retrograde cholangiopancreatography) and/or the use of patient cohorts with other diseases as controls. The objective of this study was to quantify biliary metabolites using in vivo 1 H MRS and gain insight into the pathogenesis of PSC. Biliary metabolites in 10 PSC patients and 14 healthy controls were quantified in vivo using 1 H MRS on a 3 T MR scanner. The concentrations of total bile acids plus cholesterol, glycine-conjugated bile acids, taurine-conjugated bile acids, and cholinecontaining phospholipids (chol-PLs) were compared between the two groups. There were statistically significant decreases in the levels of the above mentioned biliary metabolites in the PSC patients compared with controls. The reduction in bile acid secretion in bile of PSC patients indicates accumulation of bile acids in hepatocytes.Moreover, reduction in the levels of chol-PLs in bile may increase the toxic effects of bile acids. Our findings suggest that the bile duct injury in PSC patients is most likely due to "bile acid-induced injury." KEYWORDS choline-containing phospholipids, glycine-conjugated bile acids, human bile, in vivo 1 H MRS, L-COSY, pathogenesis, primary sclerosing cholangitis, taurine-conjugated bile acids
Fragile X syndrome (FXS) is the leading monogenetic cause of autism spectrum disorder and inherited cause of intellectual disability that affects approximately one in 7,000 males and one in 11,000 females. In FXS, the Fmr1 gene is silenced and prevents the expression of the fragile X mental retardation protein (FMRP) that directly targets mRNA transcripts of multiple GABAA subunits. Therefore, FMRP loss adversely impacts the neuronal firing of the GABAergic system which creates an imbalance in the excitatory/inhibitory ratio within the brain. Current FXS treatment strategies focus on curing symptoms, such as anxiety or decreased social function. While treating symptoms can be helpful, incorporating non-invasive imaging to evaluate how treatments change the brain’s biology may explain what molecular aberrations are associated with disease pathology. Thus, the GABAergic system is suitable to explore developing novel therapeutic strategies for FXS. To understand how the GABAergic system may be affected by this loss-of-function mutation, GABA concentrations were examined within the frontal cortex and thalamus of 5-day-old wild type and Fmr1 knockout mice using both 1H magnetic resonance imaging (1H-MRS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our objective was to develop a reliable scanning method for neonatal mice in vivo and evaluate whether 1H-MRS is suitable to capture regional GABA concentration differences at the front end of the critical cortical period where abnormal neurodevelopment occurs due to FMRP loss is first detected. 1H-MRS quantified GABA concentrations in both frontal cortex and thalamus of wild type and Fmr1 knockout mice. To substantiate the results of our 1H-MRS studies, in vitro LC-MS/MS was also performed on brain homogenates from age-matched mice. We found significant changes in GABA concentration between the frontal cortex and thalamus within each mouse from both wild type and Fmr1 knockout mice using 1H-MRS and LC-MS/MS. Significant GABA levels were also detected in these same regions between wild type and Fmr1 knockout mice by LC-MS/MS, validating that FMRP loss directly affects the GABAergic system. Thus, these new findings support the need to develop an effective non-invasive imaging method to monitor novel GABAergic strategies aimed at treating patients with FXS.
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