Cudalbu, Cristina Ramona

Gruetter, Rolf

Kunz, Nicolas

Lanz, Bernard

Mlynárik, Vladimir

van de Looij, Yohan

Infoscience - École polytechnique fédérale de Lausanne

Imaging the in vivo effect of hyperammonemia in the rat brain: a Spectroscopic Imaging and Diffusion Tensor Imaging study Cristina Cudalbu1, Nicolas Kunz1, Bernard Lanz1, Yohan Van de Looij1, Vladimir Mlynárik1, and Rolf Gruetter1,2  1Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, 2Departments of Radiology, Universities of Lausanne and Geneva, Switzerland Objectives: Ammonia is a neurotoxin that is implicated in the pathogenesis of hepatic encephalophaty (HE). Brain edema represents a major complication. In hyperammonemic (HA) conditions, glutamine is generated in astrocytes from ammonia and glutamate in a reaction catalyzed by glutamine synthetase (GS). In vitro observations suggested that during HA, alterations in brain metabolites other than glutamine can occur (1,2). Diffusion tensor imaging (DTI) measures the relative translational motion of water proton across cell membrane, which is expressed as the ADC value. Changes in ADC reflect the presence of edema. The in vivo spatial distribution of brain metabolites can be measured using proton spectroscopic imaging (SI). The aim of the study was: 1) to assess the effects of HA per se in the rat brain by DTI; 2) to image for the first time the in vivo effect of hyperammonemia per se on 12 brain metabolites (i.e. Gln, Glu, tCr, tCho, Ins, Tau, Lac, NAA+NAAG, Lac, etc) in different brain regions and the net glutamine synthesis rates.  Methods:  Experiments were performed on a 9.4T MRI system using SD rats. NH4Cl was infused (4.5mmol/h/kg) for 6h. Diffusion tensor acquisitions were performed (3) and diffusivity values (ADC, FA) were derived from the tensor. ADC was measured in ROIs positioned in: Cortex (Cx), Striatum (St), Hippocampus (Hip) and Ventricles (Ven). Ventricles sizes were also calculated on the ADC maps with a threshold set to 10mm2/s. Metabolic maps were obtained using short-echo-time proton-spectroscopic-imaging (4).  Results:  The results are presented in Fig 1. ADC measurements showed a decrease along the infusion (6%), significant only 6 hours after infusion. In addition, an increase of the ventricles size was visible (Vbefore=18 ± 6ml, V+6h=31±13ml, p<0.05). The increase in the Gln pool at different time points during infusion was apparent from the maps. The Gln concentration increased more in cortex than in hippocampus (5.5hh of infusion 16.2± 2.7mmol/kgww Cx and 11.5±1.2mmol/kgww Hip, p=0.03). The maps of the other brain metabolites did not show any visible difference before and after ammonia infusion. From the linear fit of the time-evolution of Gln we obtained a net glutamine synthesis rate of 0.039±0.007µmol/min/g Cx and 0.024±0.007µmol/min/g Hip (p=0.05).  Discussion: We propose that HA per se induces late in time a mild brain edema, as indicated by the decrease in ADC at 6h. Nevertheless, the origin of the ventricles increase and the presence of mild brain edema remain unclear and will need further investigations. High resolution metabolic maps enabled to observe the in vivo spatial distribution of 12 metabolites in various brain structures under HA. Contrary to other models of HA associated with experimental acute liver failures (1,2), no changes in spatial distribution of metabolites were observed except for Gln. The net glutamine synthesis rates were significantly higher in the cortex than in the hippocampus.  References: [1] Zwingmann C, J Neurosci Res. 85:3429, 2007. [2] Rao KV et al, Metab Brain Dis. 16:67, 2001. [3]Kunz N, Proceedings ISMRM 2008. [4] Mlynárik V et al. Magn Reson Med. 59:52, 2008.  

Imaging the in vivo effect of hyperammonemia in the rat brain: a Spectroscopic Imaging and Diffusion Tensor Imaging study

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Imaging the in vivo effect of hyperammonemia in the rat brain: a Spectroscopic Imaging and Diffusion Tensor Imaging study

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