Human focal cerebral ischemia: evaluation of brain pH and energy metabolism with P-31 NMR spectroscopy.

Levine, Steven R.; Helpern, J. A.; Welch, K. M. A.; Linde, A. M. Q. Vande; Sawaya, K. L.; Brown, Eric E.; Ramadan, Nabih M.; Deveshwar, Rk; Ordidge, Roger J.

doi:10.1148/radiology.185.2.1410369

Cited by 84 publications

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“…After the procedure described by Levine et al, 3 the frequency area for signals from inorganic phosphate at 3.6 to 5.6 ppm relative to phosphocreatine at 0 ppm was analyzed by a single Lorentzian line with variable line width, frequency, and intensity (single-peak approach). The position of this peak was used to establish a general pH value.…”

Section: Data Processingmentioning

confidence: 99%

“…1,2 However, a reversal from acute acidosis to subacute alkalosis has been described in longitudinal studies using MRS. 3,4 Acute ischemia is expected to show a near complete depletion of energy substrates in the center of the infarct as reflected in drastically reduced levels of phosphocreatine, ATP, and increased levels of inorganic phosphate (Pi).1 Phosphocreatine is an important energy source to regenerate ATP from ADP by creatine kinase reaction. Owing to the breakdown of energy metabolism, the vast majority of total creatine (tCr) should, therefore, be unphosphorylated creatine (uCr).…”

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confidence: 99%

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Changes of pH and Energy State in Subacute Human Ischemia Assessed by Multinuclear Magnetic Resonance Spectroscopy

Zöllner

Hattingen

Singer

et al. 2015

Stroke

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Background and Purpose— In vivo changes in tissue pH and energy metabolism are key to understanding stroke pathophysiology. Our goal was to study pH changes in subacute ischemic stroke and their relation to energy metabolism, which, unlike acidosis in acute stroke, are not yet well understood. Methods— We measured tissue pH and phospholipid as well as cell energy markers, including creatine, phosphocreatine, and N -acetyl-aspartate in subacute stroke with combined 1 H and 31 P magnetic resonance spectroscopy. We included 19 patients with first-ever ischemic stroke (mean time after stroke, 6 days). We then compared metabolite concentrations in the ischemic tissue to contralateral (healthy) tissue using multivariate ANOVA to assess significant differences in metabolite levels between both tissue compartments. Results— In subacute stroke, a tissue fraction with significantly increased tissue pH was observed as compared with healthy contralateral tissue (pH, 7.09 versus 7.03; P =0.002) concurrent with splitting of the pH signal with 1 peak being more alkalotic. Furthermore, only a moderate decrease of energy-rich metabolites (phosphocreatine reduced by 17%, ATP reduced by 19%) was present, whereas total creatine was reduced by 51%. Conclusions— The finding of an alkalotic pH split in subacute ischemia is unprecedented. The pH split and only incomplete energy loss in subacute stroke suggest 2 differently viable cellular moieties, best explained by active compensatory mechanisms after acute cerebral ischemia.

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Section: Data Processingmentioning

confidence: 99%

mentioning

confidence: 99%

Changes of pH and Energy State in Subacute Human Ischemia Assessed by Multinuclear Magnetic Resonance Spectroscopy

Zöllner

Hattingen

Singer

et al. 2015

Stroke

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“…Of particular interest, phosphorous-31 ( 31 P) MRS and MRI allow the evaluation of several important aspects of high-energy phosphate metabolism, from metabolite concentrations to metabolic fluxes through ATP-generating enzymes. Since 1970s, numerous studies have employed 31 P-MRS/MRI in the investigation of a broad range of diseases such as diabetes, stroke, heart failure, and cancers (3)(4)(5)(6)(7)(8). These studies have provided invaluable insights into the role of mitochondrial metabolism in normal physiology and disease development.…”

Section: Introductionmentioning

confidence: 99%

Assessing tissue metabolism by phosphorous-31 magnetic resonance spectroscopy and imaging: a methodology review

Liu

2017

Quant. Imaging Med. Surg.

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Many human diseases are caused by an imbalance between energy production and demand.Magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) provide the unique opportunity for in vivo assessment of several fundamental events in tissue metabolism without the use of ionizing radiation. Of particular interest, phosphate metabolites that are involved in ATP generation and utilization can be quantified noninvasively by phosphorous-31 ( 31 P) MRS/MRI. Furthermore, 31 P magnetization transfer (MT) techniques allow in vivo measurement of metabolic fluxes via creatine kinase (CK) and ATP synthase. However, a major impediment for the clinical applications of 31 P-MRS/MRI is the prohibitively long acquisition time and/or the low spatial resolution that are necessary to achieve adequate signal-to-noise ratio. P-MRS/MRI techniques. Applications of these techniques to the investigation of a specific physiology/pathology will be discussed without detailed description. Interested readers are referred to recent review articles on the applications of 31 P-MRS/MRI in metabolic characterization of skeletal muscle (10-12), heart (13), brain (14), and liver (11), as well as in diseases such as cancer (15), heart failure (16), and obesity and diabetes (17,18). Historical perspectiveThe use of 31 P-MRS for metabolic investigations dates back to 1960. Cohn and Hughes were the first to obtain a high-resolution 31 P spectrum of a solution of ATP (19). In addition, they also observed a dependence of the chemical shifts of the phosphorus nuclei of ATP on the pH of the solution. In parallel to the early development of MRI methods by Lauterbur (20), the entire 1970s also witnessed the rapid advance of 31 P-MRS in metabolic investigation of a broad range of biological systems. In 1973, Moon and Richards performed the first 31 P-MRS study that measured intracellular pH in human red blood cells (21). In the following year, Henderson and colleagues obtained the first 31 P spectrum of ATP from human red blood cells (22). At the same time, the Oxford team led by Radda performed the first experiment to acquire 31 P spectra from an intact organ, i.e., the excised and superfused muscle of rat hindlimb (23). The first in vivo 31 P-MRS study was performed on mouse brain by Chance et al. (24). Within the short span of one decade, organelles including mitochondria (25,26) and chromaffin granules (27), cells including Escherichia coli (28), yeast (29), and hepatocytes (30), and organs including skeletal muscle (31,32), heart (33-35), brain (36), kidney (37), and liver (38,39) have all been studied using 31 P-MRS.It is worth noting that most of these organ studies were performed on excised organs to avoid the need for spatial localization. Although Lauterbur has demonstrated the feasibility of imaging water protons (20), it was considered impractical for 31 P imaging of living systems because of the low sensitivity and difficulties with spectral resolution.The 1980s began with the publication of two important studies that aimed a...

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“…Adult clinical studies have demonstrated brain intracellular alkalosis in areas of chronic infarction after stroke (15,16) with a significant correlation between brain alkalosis and subsequent poor clinical outcome (17). We have recently observed a similar relationship between brain intracellular alkalosis and the severity of brain injury in term infants with NE (18).…”

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N-Methyl-isobutyl-amiloride Ameliorates Brain Injury When Commenced Before Hypoxia Ischemia in Neonatal Mice

et al. 2006

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Under physiologic conditions, brain intracellular pH (pH i ) is maintained at 7.03. Rebound brain intracellular alkalosis has been observed in experimental models and adult stroke after hypoxia/ ischemia (HI). In term infants with neonatal encephalopathy (NE), an association exists between the magnitude of brain alkalosis and neurodevelopmental outcome, and there is increasing evidence to suggest that alkalosis may be deleterious to cell survival. Activation of the Na ϩ /H ϩ exchanger (NHE) is thought to be responsible for the rapid normalization of pH i and rebound alkalosis after reperfusion. We hypothesized that N-methyl-isobutyl-amiloride (MIA), an inhibitor of the NHE, would reduce brain injury in a model of neonatal HI. Seven-day-old mice underwent left carotid artery occlusion followed by exposure to 8% oxygen for 30 min (moderate insult) or 1 h (severe insult). Animals received MIA or saline 8 hourly starting 30 min before HI. Outcome was determined at 48 h by measuring viable tissue in the injured hemisphere (severe insult) or injury score and TUNEL staining (moderate insult). After the severe insult, MIA had a significant neuroprotective effect increasing forebrain tissue survival from 44% to 67%. After the moderate insult, damage was localized to the hippocampus where treatment resulted in a significant reduction in injury score and in TUNEL-positive cells. MIA was also shown to have a significant overall neuroprotective effect based on injury score after the moderate insult. Amiloride analogues are neuroprotective when commenced before HI in a mouse model. P erinatal HI affects approximately one to two per 1000 term infants per year in the United Kingdom and leads to death or severe impairment in more than 750 infants annually (1) Over the past 20 y, studies using phosphorus ( 31 P) and ( 1 H) proton magnetic resonance spectroscopy (MRS) in both infants with NE (2-4) and experimental models (5,6) have characterized the biphasic disruption of cerebral energetics that occurs in the hours after HI. These observations have led to the concept of a "therapeutic window" after HI, during which intervention may ameliorate the severity of brain injury. Recent results from the first randomized trials of mild hypothermia in term infants with NE are promising (7-9); however, considerable work is still required to optimize cooling strategies in the newborn. Furthermore, there is a growing impression that optimum neuroprotection may involve the use of more than one therapy, targeting different parts of the neurotoxic cascade.Under physiologic conditions, brain pH i is maintained at approximately 7.03; the NHE tightly regulates both pH i and cell volume by extruding protons from and taking sodium up into cells (10). A remarkable observation from the studies employing 31 P MRS in infants with NE was that during the secondary phase of energy decline occurring from 8 to 24 h after birth, brain pH i was not acidic but alkaline (pH i 7.1-7.4) (11). Some evidence suggests that excessive activation of the NHE aft...

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Human focal cerebral ischemia: evaluation of brain pH and energy metabolism with P-31 NMR spectroscopy.

Cited by 84 publications

References 0 publications

Changes of pH and Energy State in Subacute Human Ischemia Assessed by Multinuclear Magnetic Resonance Spectroscopy

Changes of pH and Energy State in Subacute Human Ischemia Assessed by Multinuclear Magnetic Resonance Spectroscopy

Assessing tissue metabolism by phosphorous-31 magnetic resonance spectroscopy and imaging: a methodology review

N-Methyl-isobutyl-amiloride Ameliorates Brain Injury When Commenced Before Hypoxia Ischemia in Neonatal Mice

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