Showing papers by "Gülin Öz published in 2013"

N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases.

Abstract: Objective This study aimed to determine if the antioxidant N-acetylcysteine (NAC) is able to alter peripheral and central redox capabilities in patients with Parkinson disease (PD) or Gaucher disease (GD). Methods The study included nondemented adult subjects: 3 with PD, 3 with GD, and 3 healthy controls. Baseline brain glutathione (GSH) concentrations were measured using 7-T magnetic resonance spectroscopy (MRS). Baseline blood reduced-to-oxidized GSH ratios were determined for each subject. Brain GSH concentrations and blood redox ratios were then determined during and at specified time points after a single, 150-mg/kg NAC infusion. Results N-acetylcysteine increased blood GSH redox ratios in those with PD and GD and healthy controls, which was followed by an increase in brain GSH concentrations in all subjects. Conclusions This is the first demonstration that with MRS, it is possible to directly measure and monitor increases in brain GSH levels in the human brain in response to a single, intravenous administration of NAC. This work shows the potential utility of MRS monitoring, which could assist in determining dosing regimens for clinical trials of this potentially useful antioxidant therapy for PD disease, GD, and other neurodegenerative disorders.

Non-invasive measurement of cerebral oxygen metabolism in the mouse brain by ultra-high field 17O MR spectroscopy

Abstract: To assess cerebral energetics in transgenic mouse models of neurologic disease, a robust, efficient, and practical method for quantification of cerebral oxygen consumption is needed. 17O magnetic resonance spectroscopy (MRS) has been validated to measure cerebral metabolic rate of oxygen (CMRO2) in the rat brain; however, mice present unique challenges because of their small size. We show that CMRO2 measurements with 17O MRS in the mouse brain are highly reproducible using 16.4 Tesla and a newly designed oxygen delivery system. The method can be utilized to measure mitochondrial function in mice quickly and repeatedly, without oral intubation, and has numerous potential applications to study cerebral energetics.

Metabolomic analysis of cerebrospinal fluid indicates iron deficiency compromises cerebral energy metabolism in the infant monkey.

Abstract: Iron deficiency anemia affects many pregnant women and young infants worldwide. The health impact is significant, given iron’s known role in many body functions, including oxidative and lipid metabolism, protein synthesis and brain neurochemistry. The following research determined if 1H NMR spectroscopy-based metabolomic analysis of cerebrospinal fluid (CSF) could detect the adverse influence of early life iron deficiency on the central nervous system. Using a controlled dietary model in 43 infant primates, distinct differences were found in spectra acquired at 600 MHz from the CSF of anemic monkeys. Three metabolite ratios, citrate/pyruvate, citrate/lactate and pyruvate/glutamine ratios, differed significantly in the iron deficient infant and then normalized following the consumption of dietary iron and improvement of clinical indices of anemia in the heme compartment. This distinctive metabolomic profile associated with anemia in the young infant indicates that CSF can be employed to track the neurological effects of iron deficiency and benefits of iron supplementation.

Non-invasive detection of neurochemical changes prior to overt pathology in a mouse model of spinocerebellar ataxia type 1

Abstract: Spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of autosomal dominantly inherited neurodegenerative diseases characterized by loss of cerebellar Purkinje cells (PCs) (Schols et al. 2004). Six SCA subtypes, including SCA1, are caused by CAG trinucleotide repeat expansions in the respective genes, resulting in polyglutamine expansions in the expressed proteins (Zoghbi and Orr 2000). Cerebellar and, in many cases, brainstem degeneration in SCAs result in progressive loss of motor coordination and affect gaze, speech, gait and balance. As with all neurodegenerative diseases, there is a great need for biomarkers to monitor disease onset and progression directly in the brain. In particular, outcome measures that are complementary to clinical scales are needed (Klockgether 2011) to evaluate the effects of potential therapies in the brain (Klockgether and Paulson 2011). Successful implementation of such interventions will be facilitated by early detection of cerebellar abnormalities, potentially preceding clinical abnormalities. To this end, we have previously demonstrated the sensitivity of 1H magnetic resonance spectroscopy (MRS) to progressive neurodegeneration in a transgenic mouse model of SCA1 (Ӧz et al. 2010b). That model, designated as the SCA1[82Q] line, over-expresses the mutant human ataxin-1 protein with an 82 glutamine stretch under the control of a PC specific promoter (Burright et al. 1995) and displays neuronal dysfunction apparent as dendritic atrophy starting at 6 weeks. Neurodegeneration in the SCA1[82Q] line progresses to severe cerebellar pathology by 1 year. A subset of the neurochemicals detected by 1H MRS (N-acetylaspartate, myo-inositol and glutamate) showed progressive alterations relative to control mice and significantly correlated with pathology scores in our study using the SCA1[82Q] mice (Ӧz et al. 2010b). Remarkably, the same neurochemicals also correlated with the ataxia score in patients (Ӧz et al. 2010a), indicating these metabolites as biomarkers of disease progression and substantiating an ability to translate the mouse findings to patients. In the SCA1[82Q] model, we identified another set of neurochemicals (total creatine, glutamine, and taurine) that marked the earliest biochemical changes. Namely, these metabolites were altered in the SCA1[82Q] mice at 6 weeks, but converged with the levels of control groups as the animals aged. In a separate study, we utilized conditional expression of the transgene in SCA1[82Q] mice to establish the sensitivity of MRS biomarkers to disease reversal (Ӧz et al. 2011). While the SCA1[82Q] line was highly valuable to demonstrate the sensitivity of 1H MRS measures to progressive neurodegeneration in SCA1, this line expresses the mutant ataxin-1 mRNA at around 50–100 times endogenous levels in PCs, therefore the disease is restricted to PCs and a cerebellar phenotype, and the mice live a normal life span. On the other hand, patients with SCA1 also develop non-cerebellar, e.g. cognitive, bulbar motor and even extrapyramidal features as the disease progresses, and die prematurely. To overcome the limitations of the transgenic SCA1 model and to guarantee accurate temporal and spatial expression patterns at endogenous levels, a knock-in mouse model of SCA1 was developed whereby the human mutation was introduced into the corresponding mouse gene (Watase et al. 2002): The Sca1154Q/2Q line has a 154 polyglutamine repeat in the endogenous ataxin-1 protein (the mouse Sca1 gene contains two CAGs at this site while the rest of the gene is highly homologous to the human SCA1 gene). These mice have learning and memory deficits and suffer muscle wasting and premature death similar to human patients. In addition, PC loss occurs only at the end stage of disease and the cerebellar pathology is milder than the transgenic SCA1[82Q] mice. Therefore, we expanded our correlative MRS and histology work into the knock-in line to take advantage of these features of the Sca1154Q/2Q mice, in particular the milder cerebellar pathology. We hypothesized that metabolite levels measured by ultra-high field MRS would be sensitive to disease even prior to the development of clear pathological changes. To test this hypothesis, we compared the cerebellar neurochemical profiles of Sca1154Q/2Q mice longitudinally to those of wild-type (WT) littermates and assessed the cerebella of the mice at the same time points by histology.

Animal models and high field imaging and spectroscopy

Abstract: A plethora of magnetic resonance (MR) techniques developed in the last two decades provide unique and noninvasive measurement capabilities for studies of basic brain function and brain diseases in humans. Animal model experiments have been an indispensible part of this development. MR imaging and spectroscopy measurements have been employed in animal models, either by themselves or in combination with complementary and often invasive techniques, to enlighten us about the information content of such MR methods and/or verify observations made in the human brain. They have also been employed, with or independently of human efforts, to examine mechanisms underlying pathological developments in the brain, exploiting the wealth of animal models available for such studies. In this endeavor, the desire to push for ever-higher spatial and/or spectral resolution, better signal-to-noise ratio, and unique image contrast has inevitably led to the introduction of increasingly higher magnetic fields. As a result, today, animal model studies are starting to be conducted at magnetic fields ranging from ~ 11 to 17 Tesla, significantly enhancing the armamentarium of tools available for the probing brain function and brain pathologies.

Diabetes: Does lactate sustain brain metabolism during hypoglycaemia?

Abstract: At very low glucose levels, the cognitive function of patients with diabetes mellitus and recurrent iatrogenic hypoglycaemia is often better than that of hypoglycaemia-naive individuals. A new study shows that the brain adapts to recurrent hypoglycaemia by increasing uptake of glucose and lactate, with preferential shuttling of glucose to neurons.

CHAPTER 8:In Vivo Proton MR Spectroscopy: Animal and Human Applications at High Fields

Abstract: This chapter provides an overview about the feasibility of non‐invasive neurochemical profiling by in vivo 1H NMR spectroscopy (MRS) at high magnetic fields. The first part is focused on methodology and specific requirements for data acquisition, data processing and metabolite quantification at high‐fields. The second part presents examples of application studies using proton MRS for neurochemical profiling in animals and humans. These selected examples demonstrate the potential of this non‐invasive method in drug discovery and development research.