Non-Invasive Methods for Studying Brain Energy Metabolism: What They Show and What It Means

Kemp, Graham J.

doi:10.1159/000017471

Cited by 90 publications

(86 citation statements)

References 116 publications

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“…The high energy demand in the brain results in fast chemical cycling among cellular ATP, ADP, and Pi, which requires rapid energy transportation between the cytosol and mitochondria. This can be accomplished by PCr through the reversible CK reactions that can facilitate the effective transport of ATP from mitochondria to sites of energy utilization and vice versa for ADP (8,23). Thus, a close coupling between the CK reaction flux and the brain activity level could exist in a wide range of brain activity levels.…”

Section: Discussionmentioning

confidence: 99%

“…The brain ATP metabolism is mainly controlled by ATPase and creatine kinase (CK) reactions that are coupled together and constitute a complex chemical exchange system involving ATP, phosphocreatine (PCr), and intracellular inorganic phosphate (Pi) (i.e., a PCr^ATP^Pi chemical exchange system) (7)(8)(9)(10). One vital function of this ATP metabolic network is to maintain a stable cellular ATP concentration by adjusting the reaction rates to ensure a continuous energy supply for sustaining electrophysiological activity and maintaining normal function in the brain.…”

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confidence: 99%

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Tightly coupled brain activity and cerebral ATP metabolic rate

Zhu

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

186

220

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A majority of ATP in the brain is formed in the mitochondria through oxidative phosphorylation of ADP with the F1F0-ATP (ATPase) enzyme. This ATP production rate plays central roles in brain bioenergetics, function and neurodegeneration. In vivo 31 P magnetic resonance spectroscopy combined with magnetization transfer (MT) is the sole approach able to noninvasively determine this ATP metabolic rate via measuring the forward ATPase reaction flux (F f,ATPase). However, previous studies indicate lack of quantitative agreement between F f,ATPase and oxidative metabolic rate in heart and liver. In contrast, recent work has shown that F f,ATPase might reflect oxidative phosphorylation rate in resting human brains. We have conducted an animal study, using rats under varied brain activity levels from light anesthesia to isoelectric state, to examine whether the in vivo 31 P MT approach is suitable for measuring the oxidative phosphorylation rate and its change associated with varied brain activity. Our results conclude that the measured F f,ATPase reflects the oxidative phosphorylation rate in resting rat brains, that this flux is tightly correlated to the change of energy demand under varied brain activity levels, and that a significant amount of ATP energy is required for ''housekeeping'' under the isoelectric state. These findings reveal distinguishable characteristics of ATP metabolism between the brain and heart, and they highlight the importance of in vivo 31 P MT approach to potentially provide a unique and powerful neuroimaging modality for noninvasively studying the cerebral ATP metabolic network and its central role in bioenergetics associated with brain function, activation, and diseases.A denosine triphosphate (ATP), a high-energy phosphate (HEP) compound, is the universal energy currency in living cells for supporting the energy needs of various cellular activities and functions. In the brain, a majority of ATP is formed in the mitochondria through oxidative phosphorylation of adenosine diphosphate (ADP) catalyzed by the enzyme of ATP synthase (ATPase) (1). A large portion of ATP energy is used in cytosol to pump sodium and potassium across the cellular membrane for maintaining transmembrane ion gradients and to support neurotransmitters cycling and, thus, sustaining electrophysiological activity and cell signaling in the brain. The ATP metabolism regulating both ATP production and utilization plays a fundamental role in cerebral bioenergetics, brain function, and neurodegenerative diseases (2-6).The brain ATP metabolism is mainly controlled by ATPase and creatine kinase (CK) reactions that are coupled together and constitute a complex chemical exchange system involving ATP, phosphocreatine (PCr), and intracellular inorganic phosphate (Pi) (i.e., a PCr^ATP^Pi chemical exchange system) (7-10). One vital function of this ATP metabolic network is to maintain a stable cellular ATP concentration by adjusting the reaction rates to ensure a continuous energy supply for sustaining electrophysiological activity and ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Tightly coupled brain activity and cerebral ATP metabolic rate

Zhu

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

186

220

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“…[28][29][30][31][32][33][34][35] In general, cerebral bioenergetics underlying brain function is not readily accessible noninvasively, and how we probe it (technically) can influence our findings (the outcomes). 36 For instance, many conclusions resulting from in vitro or ex vivo studies may not be valid in the living brain. It is thus essential to use nondestructive in vivo approaches for studying the brain, especially human brain, where elimination of any invasive procedures is strongly desirable.…”

Section: H Relaxation In Watermentioning

confidence: 99%

In vivo17O NMR approaches for brain study at high field

et al. 2005

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17 O is the only stable oxygen isotope that can be detected by NMR. The quadrupolar moment of 17 O spin (I ¼ 5/2) can interact with local electric field gradients, resulting in extremely short T 1 and T 2 relaxation times which are in the range of several milliseconds. One unique NMR property of 17 O spin is the independence of 17 O relaxation times on the magnetic field strength, and this makes it possible to achieve a large sensitivity gain for in vivo 17 O NMR applications at high fields.In vivo 17 O NMR has two major applications for studying brain function and cerebral bioenergetics. The first application is to measure the cerebral blood flow (CBF) through monitoring the washout of inert H 2 17 O tracer in the brain tissue following an intravascular bolus injection of the 17 O-labeled water. The second application, perhaps the most important one, is to determine the cerebral metabolic rate of oxygen utilization (CMRO 2 ) through monitoring the dynamic changes of metabolically generated H O is a stable oxygen isotope that has a magnetic moment and can be detected by NMR. Compared with nuclei such as 1 H, 31 P and 13 C that are commonly used for most in vivo MR applications, 17 O has a spin quantum number of greater than ½ (I ¼ 5/2) and possesses an electric quadrupolar moment. The natural abundance of 17 O is only 0.037%, which is almost 30 times lower than that of 13 C and 2700 times lower than that of 1 H. Moreover, the magnetogyric ratio ( ) of 17 O, which is proportional to the Larmor frequency, is 7.4 times lower than that of 1 H.

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“…This peak is a composite of overlapping creatine and phosphocreatine resonances, representing the high-energy phosphate reserves in the cytosol of neurons and glia (21,49). Creatine's elevation in 1 H-MRS has been attributed to altered metabolism (50).…”

Section: Creatinementioning

confidence: 99%

Lateralized Caudate Metabolic Abnormalities in Adolescent Major Depressive Disorder: A Proton MR Spectroscopy Study

Gabbay

Hess

Liu

et al. 2007

AJP

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Objective-Proton magnetic resonance spectroscopy ( 1 H-MRS) has been increasingly used to examine striatal neurochemistry in adult major depressive disorder. This study extends the use of this modality to pediatric major depression to test the hypothesis that adolescents with major depression have elevated concentrations of striatal choline and creatine and lower concentrations of N-acetylaspartate.Method-Fourteen adolescents (ages 12-19 years, eight female) who had major depressive disorder for at least 8 weeks and a severity score of 40 or higher on the Children's Depression Rating Scale -Revised and 10 healthy comparison adolescents (six female) group-matched for gender, age, and handedness were enrolled. All underwent three-dimensional 3-T 1 H-MRS at high spatial resolution (0.75-cm 3 voxels). Relative levels of choline, creatine, and N-acetylaspartate in the left and right caudate, putamen, and thalamus were scaled into concentrations using phantom replacement, and levels were compared for the two cohorts.Results-Relative to comparison subjects, adolescents with major depressive disorder had significantly elevated concentrations of choline (2.11 mM versus 1.56 mM) and creatine (6.65 mM versus 5.26 mM) in the left caudate. No other neurochemical differences were observed between the groups.Conclusions-These findings most likely reflect accelerated membrane turnover and impaired metabolism in the left caudate. The results are consistent with prior imaging reports of focal and lateralized abnormalities in the caudate in adult major depression.Rates of major depressive disorder rise dramatically in adolescence, with an estimated lifetime prevalence of 15% in adolescents by ages 15-18. Major depression is associated with significant morbidity, including deterioration in academic functioning, increased risk of substance use, and attempted and completed suicides (1,2). Furthermore, adolescent major depression is a strong predictor of major depression in adulthood, which carries its own burden of disadvantage (3). These findings highlight the need for specific neurobiological research in adolescent major depression.Converging lines of evidence suggest that the pathophysiology of depression entails impairment of cellular resilience and neuroplasticity in specific cortical, subcortical, and limbic brain regions. The relationship between the basal ganglia and depression has been inferred from the high comorbidity between depression and Parkinson's disease as well as Huntington's NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript disease, both basal ganglia-related disorders. In addition, morphometric studies (but not all) and functional neuroimaging studies have documented smaller caudate, putamen, and thalamus as well as impaired metabolism and blood flow in the striatum and thalamus in depression (4-10).Proton magnetic resonance spectroscopy ( 1 H-MRS) has provided additional evidence for the involvement of the striatum in adult major depression. 1 H-MRS provides metabolic assay of ne...

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Non-Invasive Methods for Studying Brain Energy Metabolism: What They Show and What It Means

Cited by 90 publications

References 116 publications

Tightly coupled brain activity and cerebral ATP metabolic rate

Tightly coupled brain activity and cerebral ATP metabolic rate

In vivo17O NMR approaches for brain study at high field

Lateralized Caudate Metabolic Abnormalities in Adolescent Major Depressive Disorder: A Proton MR Spectroscopy Study

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