Gülin Öz

Bio: Gülin Öz is an academic researcher from University of Minnesota. The author has contributed to research in topics: Spinocerebellar ataxia & Neurochemical. The author has an hindex of 38, co-authored 110 publications receiving 4355 citations.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders

Abstract: MR spectroscopy is used worldwide as an adjunct to MR imaging in several common neurologic diseases, including brain neoplasms, inherited metabolic disorders, demyelinating disorders, and infective focal lesions.

In vivo 1H NMR spectroscopy of the human brain at high magnetic fields: metabolite quantification at 4T vs. 7T.

Abstract: A comprehensive comparative study of metabolite quantification from the human brain was performed on the same 10 subjects at 4T and 7T using MR scanners with identical consoles, the same type of RF coils, and identical pulse sequences and data analysis. Signal-to-noise ratio (SNR) was increased by a factor of 2 at 7T relative to 4T in a volume of interest selected in the occipital cortex using half-volume quadrature radio frequency (RF) coils. Spectral linewidth was increased by 50% at 7T, which resulted in a 14% increase in spectral resolution at 7T relative to 4T. Seventeen brain metabolites were reliably quantified at both field strengths. Metabolite quantification at 7T was less sensitive to reduced SNR than at 4T. The precision of metabolite quantification and detectability of weakly represented metabolites were substantially increased at 7T relative to 4T. Because of the increased spectral resolution at 7T, only one-half of the SNR of a 4T spectrum was required to obtain the same quantification precision. The Cramer-Rao lower bounds (CRLB), a measure of quantification precision, of several metabolites were lower at both field strengths than the intersubject variation in metabolite concentrations, which resulted in a strong correlation between metabolite concentrations of individual subjects measured at 4T and 7T.

Methodological consensus on clinical proton MRS of the brain: Review and recommendations

Abstract: Proton MRS (1 H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi-adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0 ) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.

Neuroglial Metabolism in the Awake Rat Brain: CO2 Fixation Increases with Brain Activity

Abstract: Glial cells are thought to supply energy for neurotransmission by increasing nonoxidative glycolysis; however, oxidative metabolism in glia may also contribute to increased brain activity. To study glial contribution to cerebral energy metabolism in the unanesthetized state, we measured neuronal and glial metabolic fluxes in the awake rat brain by using a double isotopic-labeling technique and a two-compartment mathematical model of neurotransmitter metabolism. Rats (n = 23) were infused simultaneously with 14C-bicarbonate and [1-13C]glucose for up to 1 hr. The 14C and 13C labeling of glutamate, glutamine, and aspartate was measured at five time points in tissue extracts using scintillation counting and 13C nuclear magnetic resonance of the chromatographically separated amino acids. The isotopic 13C enrichment of glutamate and glutamine was different, suggesting significant rates of glial metabolism compared with the glutamate-glutamine cycle. Modeling the 13C-labeling time courses alone and with 14C confirmed significant glial TCA cycle activity (V(PDH)((g)), approximately 0.5 micromol x gm(-1) x min(-1)) relative to the glutamate-glutamine cycle (V(NT)) (approximately 0.5-0.6 micromol x gm(-1) x min(-1)). The glial TCA cycle rate was approximately 30% of total TCA cycle activity. A high pyruvate carboxylase rate (V(PC), approximately 0.14-0.18 micromol x gm(-1) x min(-1)) contributed to the glial TCA cycle flux. This anaplerotic rate in the awake rat brain was severalfold higher than under deep pentobarbital anesthesia, measured previously in our laboratory using the same 13C-labeling technique. We postulate that the high rate of anaplerosis in awake brain is linked to brain activity by maintaining glial glutamine concentrations during increased neurotransmission.

Short-echo, single-shot, full-intensity proton magnetic resonance spectroscopy for neurochemical profiling at 4 T: Validation in the cerebellum and brainstem

Abstract: Short echo time (TE) 1H MR spectroscopy techniques are critical for extending the neurochemical information beyond NAA, creatine and choline as they facilitate the detection of brain metabolites with J-coupled spin systems, such as glutamate and glutamine. Short TE minimizes signal loss due to J-evolution and T2 relaxation, which is especially detrimental at high fields in the human brain where T2 values are relatively short (1,2). Neurochemical profiles have so far been mostly quantified using localization with the ultra-short TE stimulated-echo acquisition mode (STEAM) sequence (3–5), because T2 relaxation and J-evolution are negligible at ultra-short TE making metabolite quantification straightforward. However, the STEAM sequence utilizes only half of the available Mz magnetization, which limits the achievable spatial resolution of MRS that permits reliable metabolite quantification. Using the STEAM sequence to acquire spectra from small volumes in deep brain regions is even more difficult because the intrinsic sensitivity of volume RF coils is substantially lower than surface coils. While reasonably short TEs can be achieved with point resolved spectroscopy (PRESS) sequences that also utilize the full available Mz magnetization (6,7), the limited bandwidth of 180° refocusing pulses in these sequences may result in substantial chemical shift displacement errors at high fields. Recently, a new localization pulse sequence termed SPECIAL (spin echo full intensity acquired localization) was introduced (8), which enables full signal intensity acquisition at ultra-short TEs. The feasibility of obtaining neurochemical profiles with the SPECIAL sequence was successfully demonstrated in the rat (9) and human (10) brain. However, localization with this hybrid ISIS/spin echo sequence relies on an add-subtract scheme. Single-shot methods simplify frequency and phase correction of individual FIDs (11) and are therefore desirable for localized spectroscopy, especially in clinical populations where motion artifacts are frequently encountered (12). The localization by adiabatic selective refocusing (LASER) sequence (13) is a single-shot technique and also enables localization with full signal intensity, but requires relatively longer TEs because of 3 pairs of adiabatic 180° pulses. The TE of the LASER sequence can be shortened by replacing one of the 180° pairs by a slice selective excitation pulse in the so-called semi-LASER sequence (14), which enables TEs as short as 30 ms with a surface coil and 50 ms with a volume coil at 7T (15). The LASER sequence has the advantage that apparent T2 relaxation times of metabolites are longer than those measured with conventional Hahn spin echo sequences (1), resulting in less signal attenuation at longer TEs. In addition, J-evolution is partially suppressed in LASER due to the series of 180° pulses, also favoring signal retention. Further shortening of the TE of semi-LASER is desirable, especially for volume RF coils as the limited B1(max) of these coils require longer RF pulses. In addition, neurochemical profiles obtained at the longer TEs of semi-LASER relative to STEAM need to be validated in multiple brain regions such that the sequence can be utilized for neurochemical profiling in clinical populations. Specifically, the acceptability of approximations, such as neglecting a correction for T2 relaxation, needs to be investigated for absolute metabolite quantification. The aims of this study were 1) to design and optimize a single-shot, semi-adiabatic localization method with full signal intensity, short TE and minimal chemical shift displacement error and 2) to validate neurochemical profiling using this new sequence in multiple, clinically relevant brain regions in humans. To achieve these goals, we modified the semi-LASER sequence to minimize TE and then tested its performance at 4T with a surface and a volume RF coil. To validate neurochemical profiles obtained with the newly developed semi-LASER sequence, we compared neurochemical profiles quantified from semi-LASER and STEAM spectra acquired from the cerebellum and brainstem, brain regions affected in various movement disorders (16).

International Consensus on Use of Continuous Glucose Monitoring

Abstract: Measurement of glycated hemoglobin (HbA1c) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use (rtCGM) or intermittently viewed (iCGM), addresses many of the limitations inherent in HbA1c testing and self-monitoring of blood glucose. Although both provide the means to move beyond the HbA1c measurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to the most appropriate glucose monitoring methodologies, as well as standardized advice about how best to use the new information they provide, have yet to be established. In February 2017, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address these issues. This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes.

Glial regulation of the cerebral microvasculature

Abstract: The brain is a heterogeneous organ with regionally varied and constantly changing energetic needs. Blood vessels in the brain are equipped with control mechanisms that match oxygen and glucose delivery through blood flow with the local metabolic demands that are imposed by neural activity. However, the cellular bases of this mechanism have remained elusive. A major advance has been the demonstration that astrocytes, cells with extensive contacts with both synapses and cerebral blood vessels, participate in the increases in flow evoked by synaptic activity. Their organization in nonoverlapping spatial domains indicates that they are uniquely positioned to shape the spatial distribution of the vascular responses that are evoked by neural activity. Astrocytic calcium is an important determinant of microvascular function and may regulate flow independently of synaptic activity. The involvement of astrocytes in neurovascular coupling has broad implications for the interpretation of functional imaging signals and for the understanding of brain diseases that are associated with neurovascular dysfunction.

Emerging applications of metabolomics in drug discovery and precision medicine

Abstract: Metabolomics is an emerging 'omics' science involving the comprehensive characterization of metabolites and metabolism in biological systems. Recent advances in metabolomics technologies are leading to a growing number of mainstream biomedical applications. In particular, metabolomics is increasingly being used to diagnose disease, understand disease mechanisms, identify novel drug targets, customize drug treatments and monitor therapeutic outcomes. This Review discusses some of the latest technological advances in metabolomics, focusing on the application of metabolomics towards uncovering the underlying causes of complex diseases (such as atherosclerosis, cancer and diabetes), the growing role of metabolomics in drug discovery and its potential effect on precision medicine.

The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer.

Abstract: Neurons are metabolically handicapped in the sense that they are not able to perform de novo synthesis of neurotransmitter glutamate and γ-aminobutyric acid (GABA) from glucose. A metabolite shuttle known as the glutamate/GABA-glutamine cycle describes the release of neurotransmitter glutamate or GABA from neurons and subsequent uptake into astrocytes. In return, astrocytes release glutamine to be taken up into neurons for use as neurotransmitter precursor. In this review, the basic properties of the glutamate/GABA-glutamine cycle will be discussed, including aspects of transport and metabolism. Discussions of stoichiometry, the relative role of glutamate vs. GABA and pathological conditions affecting the glutamate/GABA-glutamine cycling are presented. Furthermore, a section is devoted to the accompanying ammonia homeostasis of the glutamate/GABA-glutamine cycle, examining the possible means of intercellular transfer of ammonia produced in neurons (when glutamine is deamidated to glutamate) and utilized in astrocytes (for amidation of glutamate) when the glutamate/GABA-glutamine cycle is operating. A main objective of this review is to endorse the view that the glutamate/GABA-glutamine cycle must be seen as a bi-directional transfer of not only carbon units but also nitrogen units.

Biomarkers of Nutrition for Development (BOND)-Iron Review.

Abstract: The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development.