104 research outputs found
Longitudinal osmotic and neurometabolic changes in young rats with chronic cholestatic liver disease.
Type C hepatic encephalopathy (type C HE) is increasingly suspected in children with chronic liver disease (CLD), and believed to underlie long-term neurocognitive difficulties. The molecular underpinnings of type C HE in both adults and children are incompletely understood. In the present study we combined the experimental advantages of in vivo high field <sup>1</sup> H magnetic resonance spectroscopy with immunohistochemistry to follow longitudinally over 8 weeks the neurometabolic changes in the hippocampus of animals having undergone bile duct ligation as pups. Rats who develop CLD early in life displayed pronounced neurometabolic changes in the hippocampus characterized by a progressive increase in glutamine concentration which correlated with plasma ammonia levels and a rapid decrease in brain myo-inositol. Other neurometabolic findings included a decrease in other organic osmolytes (taurine, choline-containing compounds and creatine), ascorbate and glutamate. At the cellular level, we observed an increase in glial fibrillary acidic protein (GFAP) and aquaporin 4 (AQP4) expression in the hippocampus at 4 weeks post bile duct ligation (BDL), together with astrocytic morphological alterations. These findings differ from observations in the brain of adult rats following BDL, and are in keeping with the commonly accepted theory of age-dependent vulnerability
Neurometabolic changes in a rat pup model of type C hepatic encephalopathy depend on age at liver disease onset.
Chronic liver disease (CLD) is a serious condition where various toxins present in the blood affect the brain leading to type C hepatic encephalopathy (HE). Both adults and children are impacted, while children may display unique vulnerabilities depending on the affected window of brain development.We aimed to use the advantages of high field proton Magnetic Resonance Spectroscopy ( <sup>1</sup> H MRS) to study longitudinally the neurometabolic and behavioural effects of Bile Duct Ligation (animal model of CLD-induced type C HE) on rats at post-natal day 15 (p15) to get closer to neonatal onset liver disease. Furthermore, we compared two sets of animals (p15 and p21-previously published) to evaluate whether the brain responds differently to CLD according to age onset.We showed for the first time that when CLD was acquired at p15, the rats presented the typical signs of CLD, i.e. rise in plasma bilirubin and ammonium, and developed the characteristic brain metabolic changes associated with type C HE (e.g. glutamine increase and osmolytes decrease). When compared to rats that acquired CLD at p21, p15 rats did not show any significant difference in plasma biochemistry, but displayed a delayed increase in brain glutamine and decrease in total-choline. The changes in neurotransmitters were milder than in p21 rats. Moreover, p15 rats showed an earlier increase in brain lactate and a different antioxidant response. These findings offer tentative pointers as to which neurodevelopmental processes may be impacted and raise the question of whether similar changes might exist in humans but are missed owing to <sup>1</sup> H MRS methodological limitations in field strength of clinical magnet
High field brain proton magnetic resonance spectroscopy and volumetry in children with chronic, compensated liver disease - A pilot study.
There is increasing evidence that children or young adults having acquired liver disease in childhood display neurocognitive impairment which may become more apparent as they grow older. The molecular, cellular and morphological underpinnings of this clinical problem are incompletely understood.
Therefore, we used the advantages of highly-resolved proton magnetic resonance spectroscopy at ultra-high magnetic field to analyze the neurometabolic profile and brain morphometry of children with chronic, compensated liver disease, hypothesizing that with high field spectroscopy we would identify early evidence of rising brain glutamine and decreased myoinositol, such as has been described both in animals and humans with more significant liver disease.
Patients (n = 5) and age-matched controls (n = 19) underwent 7T MR scans and short echo time <sup>1</sup> H MR spectra were acquired using the semi-adiabatic SPECIAL sequence in two voxels located in gray and white matter dominated prefrontal cortex, respectively. A 3D MP2RAGE sequence was also acquired for brain volumetry and T <sub>1</sub> mapping. Liver disease had to have developed at least 6 months before entering the study. Subjects underwent routine blood analysis and neurocognitive testing using validated methods within 3 months of MRI and MRS.
Five children aged 8-16 years with liver disease acquired in childhood were included. Baseline biological characteristics were similar among patients. There were no statistically significant differences between subjects and controls in brain metabolite levels or brain volumetry. Finally, there were minor neurocognitive fluctuations including attention deficit in one child, but none fell in the statistically significant range.
Children with chronic, compensated liver disease did not display an abnormal neurometabolic profile, neurocognitive abnormalities, or signal intensity changes in the globus pallidus. Despite the absence of neurometabolic changes, it is an opportunity to emphasize that it is only by developing the use of <sup>1</sup> H MRS at high field in the clinical arena that we will understand the significance and generalizability of these findings in children with CLD. Healthy children displayed neurometabolic regional differences as previously reported in adult subjects
A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism.
Creatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficits and autistic-like traits. The Slc6a8 <sup>Y389C</sup> KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation
Probiotics improve the neurometabolic profile of rats with chronic cholestatic liver disease.
Chronic liver disease leads to neuropsychiatric complications called hepatic encephalopathy (HE). Current treatments have some limitations in their efficacy and tolerability, emphasizing the need for alternative therapies. Modulation of gut bacterial flora using probiotics is emerging as a therapeutic alternative. However, knowledge about how probiotics influence brain metabolite changes during HE is missing. In the present study, we combined the advantages of ultra-high field in vivo <sup>1</sup> H MRS with behavioural tests to analyse whether a long-term treatment with a multistrain probiotic mixture (VIVOMIXX) in a rat model of type C HE had a positive effect on behaviour and neurometabolic changes. We showed that the prophylactic administration of this probiotic formulation led to an increase in gut Bifidobacteria and attenuated changes in locomotor activity and neurometabolic profile in a rat model of type C HE. Both the performance in behavioural tests and the neurometabolic profile of BDL + probiotic rats were improved compared to the BDL group at week 8 post-BDL. They displayed a significantly lesser increase in brain Gln, a milder decrease in brain mIns and a smaller decrease in neurotransmitter Glu than untreated animals. The clinical implications of these findings are potentially far-reaching given that probiotics are generally safe and well-tolerated by patients
Single spin-echo T 2 relaxation times of cerebral metabolites at 14.1 T in the in vivo rat brain.
OBJECT: To determine the single spin-echo T 2 relaxation times of uncoupled and J-coupled metabolites in rat brain in vivo at 14.1 T and to compare these results with those previously obtained at 9.4 T.
MATERIALS AND METHODS: Measurements were performed on five rats at 14.1 T using the SPECIAL sequence and TE-specific basis-sets for LCModel analysis.
RESULTS AND CONCLUSION: The T 2 of singlets ranged from 98 to 148 ms and T 2 of J-coupled metabolites ranged from 72 ms (glutamate) to 97 ms (myo-inositol). When comparing the T 2s of the metabolites measured at 14.1 T with those previously measured at 9.4 T, a decreasing trend was found (p < 0.0001). We conclude that the modest shortening of T 2 at 14.1 T has a negligible impact on the sensitivity of the (1)H MRS when performed at TE shorter than 10 ms
In Vivo Longitudinal 1H MRS Study of Transgenic Mouse Models of Prion Disease in the Hippocampus and Cerebellum at 14.1 T
Brain edema in chronic hepatic encephalopathy
Brain edema is a common feature associated with hepatic encephalopathy (HE). In patients with acute HE, brain edema has been shown to play a crucial role in the associated neurological deterioration. In chronic HE, advanced magnetic resonance imaging (MRI) techniques have demonstrated that low-grade brain edema appears also to be an important pathological feature. This review explores the different methods used to measure brain edema ex vivo and in vivo in animal models and in humans with chronic HE. In addition, an in-depth description of the main studies performed to date is provided. The role of brain edema in the neurological alterations linked to HE and whether HE and brain edema are the manifestations of the same pathophysiological mechanism or two different cerebral manifestations of brain dysfunction in liver disease are still under debate. In vivo MRI/magnetic resonance spectroscopy studies have allowed insight into the development of brain edema in chronic HE. However, additional in vivo longitudinal and multiparametric/multimodal studies are required (in humans and animal models) to elucidate the relationship between liver function, brain metabolic changes, cellular changes, cell swelling, and neurological manifestations in chronic HE
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