Evaluation of early cerebral metabolic, perfusion and microstructural changes in HCV-positive patients: A pilot study
ABSTRACT BACKGROUND AND AIMS: The aim of the study was to evaluate early metabolic, perfusion and microstructural cerebral changes in patients with the hepatitis C virus (HCV) infection and normal appearing brain on plain MR using advanced MR techniques, as well as to assess correlations of MR measurements with the liver histology activity index (HAI). METHODS: Fifteen HCV-positive patients and 18 control subjects underwent single voxel MR spectroscopy (MRS), perfusion weighted imaging (PWI), diffusion tensor imaging (DTI), using a 1.5T MR unit. MRS metabolite ratios (NAA/Cr, Cho/Cr, mI/Cr) were calculated. PWI values of relative cerebral blood volume (rCBV) were assessed from 8 areas including several cortical locations, basal ganglia and fronto-parietal white matter. DTI fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained from 14 white matter tracts. RESULTS: Compared to controls, HCV-positive patients showed significantly (p < 0.05) lower NAA/Cr ratios within frontal and parietal white matters, lower rCBV values within frontal and temporo-parietal cortices, decreased FA values, as well as increased ADC values in several white matter tracts. We also found elevated rCBV values in basal ganglia regions. The increase in mI/Cr and Cho/Cr ratio was correlated with a higher HAI score. CONCLUSIONS: The results of advanced MR techniques indicate neurotoxicity of HCV reflected by neuronal impairment within white matter, cortical hypoperfusion and disintegrity within several white matter tracts. Hyperperfusion in basal ganglia may be an indicator of brain inflammation in HCV patients. Our findings may suggest a biologic link between HCV-related liver disease and cerebral dysfunction.
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ABSTRACT: Chronic inflammatory liver diseases are often accompanied by behavior alterations including fatigue, mood disorders, cognitive dysfunction and sleep disturbances. These altered behaviors can adversely affect patient quality of life. The communication pathways between the inflamed liver and the brain that mediate changes in central neural activity leading to behavior alterations during liver inflammation are poorly understood. Neural and humoral communication pathways have been most commonly implicated as driving peripheral inflammation to brain signaling. Classically, the cytokines TNFα, IL-1β and IL-6 have received the greatest scientific attention as potential mediators of this communication pathway. In mice with liver inflammation we have identified a novel immune-mediated liver-to-brain communication pathway whereby CCR2(+) monocytes found within the peripheral circulation transmigrate into the brain parenchyma in response to MCP-1/CCL2 expressing activated microglia. Inhibition of cerebral monocyte infiltration in these mice significantly improved liver inflammation associated sickness behaviors. Importantly, in recent work we have found that at an earlier time point, when cerebral monocyte infiltration is not evident in mice with liver inflammation, increased monocyte:cerebral endothelial cell adhesive interactions are observed using intravital microscopy of the brain. These monocyte:cerebral endothelial cell adhesive interactions are P-selectin mediated, and inhibition of these interactions attenuated microglial activation and sickness behavior development. Delineating the pathways that the periphery uses to communicate with the brain during inflammatory liver diseases, and the central neurotransmitter systems that are altered through these communication pathways (e.g., serotonin, corticotrophin releasing hormone) to give rise to liver inflammation-associated sickness behaviors, will allow for the identification of novel therapeutic targets to decrease the burden of debilitating symptoms in these patients.Brain Behavior and Immunity 10/2013; 35. DOI:10.1016/j.bbi.2013.10.009 · 6.13 Impact Factor
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ABSTRACT: The pathogenesis of idiopathic growth hormone deficiency (GHD) in children, including possible cerebral metabolic alterations, remains unclear. The aim of the study was to evaluate metabolic changes within the normal appearing brain in children with GHD using MR spectroscopy (MRS) and to correlate MRS measurements with hormonal concentrations and with pituitary gland size. Methods: Seventy children with GHD (mean age 7.8yrs) and 11 healthy controls (mean age 8.4yrs) were enrolled in the study. The MRS examinations were performed on a 1.5T scanner. Voxels were located in the posterior cingulate gyrus (PCG) and the left parietal white matter (PWM). The NAA/Cr, Cho/Cr and mI/Cr ratios were analyzed. The metabolite ratios, pituitary gland size and hormonal concentrations: growth hormone (GH) in two stimulation tests and GH during the night, as well as IGF-1 (insulin-like growth factor) and IGFBP3 (insulin-like growth factor-binding protein) levels were also correlated. Results: There was a significant (p<0.05) decrease of the NAA/Cr ratios in PCG and PWM in children with GHD compared to the normal subjects. Other metabolite ratios showed no significant differences. We also found significant positive correlations between NAA/Cr ratio in PWM and IGFBP3 level, as well as with GH concentration in a stimulation test with glucagon. Conclusions: The reduction of NAA/Cr ratios may suggest loss of neuronal activity within normal appearing gray and white matters in children with GHD. MRS could be a sensitive marker of cerebral metabolic disturbances associated with GHD and maybe used as an additional indicator for therapy with recombinant GH.Brain & development 12/2013; 36(9). DOI:10.1016/j.braindev.2013.11.008 · 1.54 Impact Factor
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ABSTRACT: Neuro-psychiatric and cognitive disorders are frequent in patients with chronic hepatitis C (CHC) virus (HCV) infection which adversely impact quality of life, antiviral treatment adherence and outcome. HCV has neurotrophic properties and affects lipid metabolism, essential for cognitive function. We evaluated the relationship of lipid profiles with depression and anxiety symptoms and the effects of 12-weeks of therapy with fluvastatin and omega-3 ethyl esters (n-3 PUFA) in a randomised pilot study of CHC prior non-responders. Participants (n = 60) had fasting lipid profiles and assessment of depression and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS) questionnaire at each study visit. At screening 26/60 (43 %) had HADS-A score ≥8 and 13/60 (22 %) had HADS-D scores ≥8. Depressed patients had significantly lower apolipoprotein-E concentrations (30 mg/l vs 39 mg/l, P = 0.029) than those without depression and a tendency toward lower total cholesterol (3.8 vs 4.4 mmol/l, P = 0.053). 3 patients discontinued lipid-modifying treatment because of worsening depression. However, there was a small but significant improvement in anxiety symptoms after 12-weeks of high-dose (2-4 g daily) n-3 PUFA. In conclusion, depression in CHC is associated with plasma apoE deficiency. We postulate that apoE deficiency disrupts blood brain barrier integrity to promote HCV infection of the CNS. High-dose n-PUFAs may alleviate anxiety in some CHC patients but the use of lipid lowering therapy must be balanced against risks of worsening depression.Metabolic Brain Disease 03/2014; 29(3). DOI:10.1007/s11011-014-9520-9 · 2.40 Impact Factor