There are significant differences in cerebral metabolism between the immature and mature nervous system observed under normal and pathological conditions that affect the care and treatment of infants and children. The ability to investigate in vivo cerebral metabolism non-invasively in this age group will provide important information to both, make a more rational choice of therapy and allow one to monitor its effect. The use of in vivo NMR spectroscopy and stable isotopes with magnetic properties can furnish this information, but must be first validated in animal studies before its application to humans. The goal of this project is to establish that in vivo 1H and 13C NMR spectroscopic methods using 1-13C glucose will provide a measure of the fluxes through various pathways of carbohydrate and intermediary metabolism in the immature nervous system of the pig. The turnover of the cerebral lactate and amino acid pools in the neocortex will be measured in vivo in both the resting state and during generalized seizures. This data will be analyzed by modified computer modeling schemes previously delineated by radioisotope studies to generate a measure of the fluxes through the glycolytic and citric acid cycle pathways. These measurements will be validated both by performing high resolution NMR studies on tissue extracts in vitro and by using both glucose and lactate with the carbon label in other positions. This later method which has been well established by previous radioisotope studies will both provide a more accurate measure of the fluxes through other pathways such as the pentose cycle and pyruvate carboxylase and evaluate the use of alternative substrates by the brain. This information will then be used to refine the modeling program and allow a more accurate determination of the glycolytic and citric acid cycle fluxes from the original in vivo data. The changes of these fluxes and the use of lactate as an alternative substrate in the brain both during a generalized seizure and in the post-ictal period will be determined. The results of the experiments in this project will provide new information about the changes in metabolic fluxes occurring in the neocortex during generalized seizures in the immature nervous system. In addition, the data will be used to define the protocols required to perform similar non-invasive studies in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS028790-02
Application #
3478106
Study Section
Human Development and Aging Subcommittee 3 (HUD)
Project Start
1990-09-01
Project End
1995-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
van Zijl, P C; Rothman, D (1995) NMR studies of brain 13C-glucose uptake and metabolism: present status. Magn Reson Imaging 13:1213-21
Novotny Jr, E J; Avison, M J; Herschkowitz, N et al. (1995) In vivo measurement of phenylalanine in human brain by proton nuclear magnetic resonance spectroscopy. Pediatr Res 37:244-9
Mason, G F; Gruetter, R; Rothman, D L et al. (1995) Simultaneous determination of the rates of the TCA cycle, glucose utilization, alpha-ketoglutarate/glutamate exchange, and glutamine synthesis in human brain by NMR. J Cereb Blood Flow Metab 15:12-25
Novotny Jr, E J (1995) Overview--the role of NMR spectroscopy in epilepsy. Magn Reson Imaging 13:1171-3
Gruetter, R; Novotny, E J; Boulware, S D et al. (1992) Direct measurement of brain glucose concentrations in humans by 13C NMR spectroscopy. Proc Natl Acad Sci U S A 89:1109-12
Gruetter, R; Rothman, D L; Novotny, E J et al. (1992) Localized 13C NMR spectroscopy of myo-inositol in the human brain in vivo. Magn Reson Med 25:204-10