다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

https://www.cell.com/cell-metabolism/pdf/S1550-4131(11)00420-7.pdf

Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation

Proton NMR chemical shift and J-coupling values are presented for 35 metabolites that can be detected by in vivo or in vitro NMR studies of mammalian brain. Measurements were obtained using high-field NMR spectra of metabolites in solution, under conditions typical for normal physiological temperature and pH. This information is presented with an accuracy that is suitable for computer simulation of metabolite spectra to be used as basis functions of a parametric spectral analysis procedure. This procedure is verified by the analysis of a rat brain extract spectrum, using the measured spectral parameters. In addition, the metabolite structures and example spectra are presented, and clinical applications and MR spectroscopic measurements of these metabolites are reviewed.

http://pfeifer.phas.ubc.ca/refbase/files/Govindaraju-NMRBiomed-2000-13-129.pdf

Proton NMR chemical shifts and coupling constants for brain metabolites.

Functional brain imaging with positron emission tomography and magnetic resonance imaging has been used extensively to map regional changes in brain activity. The signal used by both techniques is based on changes in local circulation and metabolism (brain work). Our understanding of the cell biology of these changes has progressed greatly in the past decade. New insights have emerged on the role of astrocytes in signal transduction as has an appreciation of the unique contribution of aerobic glycolysis to brain energy metabolism. Likewise our understanding of the neurophysiologic processes responsible for imaging signals has progressed from an assumption that spiking activity (output) of neurons is most relevant to one focused on their input. Finally, neuroimaging, with its unique metabolic perspective, has alerted us to the ongoing and costly intrinsic activity within brain systems that most likely represents the largest fraction of the brain's functional activity.

Brain Work and Brain Imaging

Continuing improvements in analytical technology along with an increased interest in performing comprehensive, quantitative metabolic profiling, is leading to increased interest pressures within the metabolomics community to develop centralized metabolite reference resources for certain clinically important biofluids, such as cerebrospinal fluid, urine and blood. As part of an ongoing effort to systematically characterize the human metabolome through the Human Metabolome Project, we have undertaken the task of characterizing the human serum metabolome. In doing so, we have combined targeted and non-targeted NMR, GC-MS and LC-MS methods with computer-aided literature mining to identify and quantify a comprehensive, if not absolutely complete, set of metabolites commonly detected and quantified (with today's technology) in the human serum metabolome. Our use of multiple metabolomics platforms and technologies allowed us to substantially enhance the level of metabolome coverage while critically assessing the relative strengths and weaknesses of these platforms or technologies. Tables containing the complete set of 4229 confirmed and highly probable human serum compounds, their concentrations, related literature references and links to their known disease associations are freely available at http://www.serummetabolome.ca.

/pdf/the-human-serum-metabolome-52a86bwnf3.pdf

The Human Serum Metabolome

In the last 25 years, (13)C MRS has been established as the only noninvasive method for the measurement of glutamate neurotransmission and cell-specific neuroenergetics. Although technically and experimentally challenging, (13)C MRS has already provided important new information on the relationship between neuroenergetics and neuronal function, the energy cost of brain function, the high neuronal activity in the resting brain state and how neuroenergetics and neurotransmitter cycling are altered in neurological and psychiatric disease. In this article, the current state of (13)C MRS as it is applied to the study of neuroenergetics and neurotransmitter cycling in humans is reviewed. The focus is predominantly on recent findings in humans regarding metabolic pathways, applications to clinical research and the technical status of the method. Results from in vivo (13)C MRS studies in animals are discussed from the standpoint of the validation of MRS measurements of neuroenergetics and neurotransmitter cycling, and where they have helped to identify key questions to address in human research. Controversies concerning the relationship between neuroenergetics and neurotransmitter cycling and factors having an impact on the accurate determination of fluxes through mathematical modeling are addressed. We further touch upon different (13)C-labeled substrates used to study brain metabolism, before reviewing a number of human brain diseases investigated using (13)C MRS. Future technological developments are discussed that will help to overcome the limitations of (13)C MRS, with special attention given to recent developments in hyperpolarized (13)C MRS.

/pdf/13c-mrs-studies-of-neuroenergetics-and-neurotransmitter-46mpylypra.pdf

13C MRS studies of neuroenergetics and neurotransmitter cycling in humans.

A decline in brain function is a characteristic feature of healthy aging; however, little is known about the biologic basis of this phenomenon. To determine whether there are alterations in brain mitochondrial metabolism associated with healthy aging, we combined 13C/1H magnetic resonance spectroscopy with infusions of [1-13C]glucose and [2-13C]acetate to quantitatively characterize rates of neuronal and astroglial tricarboxylic acid cycles, as well as neuroglial glutamate–glutamine cycling, in healthy elderly and young volunteers. Compared with young subjects, neuronal mitochondrial metabolism and glutamate–glutamine cycle flux was ~30% lower in elderly subjects. The reduction in individual subjects correlated strongly with reductions in N-acetylaspartate and glutamate concentrations consistent with chronic reductions in brain mitochondrial function. In elderly subjects infused with [2-13C]acetate labeling of glutamine, C4 and C3 differed from that of the young subjects, indicating age-related changes in glial mitochondrial metabolism. Taken together, these studies show that healthy aging is associated with reduced neuronal mitochondrial metabolism and altered glial mitochondrial metabolism, which may in part be responsible for declines in brain function.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2009.197

Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy

In vivo NMR spectroscopy

MR offers unique tools for measuring molecular diffusion. This review focuses on the use of diffusion-weighted MR spectroscopy (DW-MRS) to non-invasively quantitate the translational displacement of endogenous metabolites in intact mammalian tissues. Most of the metabolites that are observed by in vivo MRS are predominantly located in the intracellular compartment. DW-MRS is of fundamental interest because it enables one to probe the in situ status of the intracellular space from the diffusion characteristics of the metabolites, while at the same time providing information on the intrinsic diffusion properties of the metabolites themselves. Alternative techniques require the introduction of exogenous probe molecules, which involves invasive procedures, and are also unable to measure molecular diffusion in and throughout intact tissues. The length scale of the process(es) probed by MR is in the micrometer range which is of the same order as the dimensions of many intracellular entities. DW-MRS has been used to estimate the dimensions of the cellular elements that restrict intracellular metabolite diffusion in muscle and nerve tissue. In addition, it has been shown that DW-MRS can provide novel information on the cellular response to pathophysiological changes in relation to a range of disorders, including ischemia and excitotoxicity of the brain and cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/nbm.686

Diffusion NMR spectroscopy.

Currently, the only widely available metabolic imaging technique in the clinic is positron emission tomography (PET) detection of the radioactive glucose analog 2-18F-fluoro-2-deoxy-d-glucose (18FDG). However, 18FDG-PET does not inform on metabolism downstream of glucose uptake and often provides ambiguous results in organs with intrinsic high glucose uptake, such as the brain. Deuterium metabolic imaging (DMI) is a novel, noninvasive approach that combines deuterium magnetic resonance spectroscopic imaging with oral intake or intravenous infusion of nonradioactive 2H-labeled substrates to generate three-dimensional metabolic maps. DMI can reveal glucose metabolism beyond mere uptake and can be used with other 2H-labeled substrates as well. We demonstrate DMI by mapping metabolism in the brain and liver of animal models and human subjects using [6,6′-2H2]glucose or [2H3]acetate. In a rat glioma model, DMI revealed pronounced metabolic differences between normal brain and tumor tissue, with high-contrast metabolic maps depicting the Warburg effect. We observed similar metabolic patterns and image contrast in two patients with a high-grade brain tumor after oral intake of 2H-labeled glucose. Further, DMI used in rat and human livers showed [6,6′-2H2]glucose stored as labeled glycogen. DMI is a versatile, robust, and easy-to-implement technique that requires minimal modifications to existing clinical magnetic resonance imaging scanners. DMI has great potential to become a widespread method for metabolic imaging in both (pre)clinical research and the clinic.

http://advances.sciencemag.org/content/advances/4/8/eaat7314.full.pdf

Robin A. de Graaf

Papers

13C MRS studies of neuroenergetics and neurotransmitter cycling in humans.

Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy

In vivo NMR spectroscopy

Diffusion NMR spectroscopy.

Deuterium metabolic imaging (DMI) for MRI-based 3D mapping of metabolism in vivo