Abstract
Regional changes of metabolite concentrations during human brain development were assessed by quantitative localized proton magnetic resonance spectroscopy in vivo. Apart from measurements in young healthy adults, the study was based on regional spectra from 97 children who were either healthy or suffered from mental retardation, movement disorders, epilepsies, neoplasm, or vascular malformation. Metabolite quantitation focused on cortical gray and white matter, cerebellum, thalamus, and basal ganglia in six age groups from infancy to adulthood. During infancy and childhood, the concentration of the neuroaxonally located N-acetylaspartate increased in gray matter, cerebellum, and thalamus, whereas a constant level was detected in white matter. These findings are in line with regional differences in the formation of synaptic connections during early development and suggest a role of N-acetylaspartate as a marker of functioning neuroaxonal tissue rather than of the mere presence of nerve cells. This view is further supported by high concentrations of taurine in gray matter and cerebellum during infancy, because taurine is also believed to be involved in the process of synapse formation. Remarkably, in basal ganglia both N-acetylaspartate and taurine remain constant at relatively high concentrations. Other metabolite changes during maturation include increases of N-acetylaspartylglutamate, especially in thalamus and white matter, and a decrease of glutamine in white matter. Despite regional differences and some small changes during the first year of life, the concentrations of creatine, phosphocreatine, choline-containing compounds, myo-inositol, and glutamate remain constant afterward. The creatine to phosphocreatine concentration ratio yields 2:1 throughout the human brain irrespective of region or age. The observed increase of the proton resonance line-width with age is most pronounced in basal ganglia and corresponds to the age-related and tissue-dependent increase of brain iron.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- Cr:
-
creatine
- Cho:
-
choline-containing compounds
- FWHM:
-
full line-width at half maximum
- GABA:
-
γ-aminobutyric acid
- Glc:
-
glucose
- Glu:
-
glutamate
- Gln:
-
glutamine
- Ins:
-
myo-inositol
- Lac:
-
lactate
- MRS:
-
magnetic resonance spectroscopy
- NAA:
-
N-acetylaspartate
- NAAG:
-
N-acetylaspartylglutamate
- PCr:
-
phosphocreatine
- ppm:
-
parts per million
- scyllo-Ins:
-
scyllo-inositol
- SNR:
-
signal-to-noise ratio
- STEAM:
-
stimulated echo acquisition mode
- Tau:
-
taurine
- tCr:
-
total creatine
- T1:
-
spin-lattice relaxation time
- T2:
-
spin-spin relaxation time
- TE:
-
echo time
- TM:
-
mixing time
- tNAA:
-
total N-acetylaspartyl compounds
- TR:
-
repetition time
- VOI:
-
volume-of-interest
References
van der Knaap MS, van der Grond J, van Rijen PC, Faber JAJ, Valk J, Willemse K 1990 Age-dependent changes in localized proton and phosphorus MR spectroscopy of the brain. Radiology 176: 509–515.
Peden CJ, Cowan FM, Bryant DJ, Sargentoni J, Cox IJ, Menon DK, Gadian DG, Bell JD, Dubowitz LM 1990 Proton MR spectroscopy of the brain in infants. J Comput Assist Tomogr 14: 886–894.
Hüppi PS, Posse S, Lazeyras F, Burri R, Bossi E, Herschkowitz N 1991 Magnetic resonance in preterm and term newborns: 1H spectroscopy in developing human brain. Pediatr Res 30: 574–578.
Bruhn H, Kruse B, Korenke GC, Hanefeld F, Hänicke W, Merboldt KD, Frahm J 1992 Proton NMR spectroscopy of cerebral metabolic alterations in infantile peroxisomal disorders. J Comput Assist Tomogr 16: 335–344.
Kreis R, Ernst T, Ross BD 1993 Development of the human brain: in vivo quantification of metabolite and water content with proton magnetic resonance spectroscopy. Magn Reson Med 30: 424–437.
Toft PB, Leth H, Lou HC, Pryds O, Henriksen O 1994 Metabolite concentrations in the developing brain estimated with proton MR spectroscopy. J Magn Reson Imaging 4: 674–680.
Hüppi PS, Fusch C, Boesch C, Burri R, Bossi E, Amato M, Herschkowitz N 1995 Regional metabolic assessment of human brain during development by proton magnetic resonance spectroscopy in vivo and by high-performance liquid chromatography/gas chromatography in autopsy tissue. Pediatr Res 37: 145–150.
Hashimoto T, Tayama M, Miyazaki M, Fujii E, Harada M, Miyoshi H, Tanouchi M, Kuroda Y 1995 Developmental brain changes investigated with proton magnetic resonance spectroscopy. Dev Med Child Neurol 37: 398–405.
Kimura H, Fujii Y, Itoh S, Matsuda T, Iwasaki T, Maeda M, Konishi Y, Ishii Y 1995 Metabolic alterations in the neonate and infant brain during development: : evaluation with proton MR spectroscopy. Radiology 194: 483–489.
Frahm J, Hanefeld F 1996 Localized proton magnetic resonance spectroscopy of cerebral metabolites. Neuropediatrics 27: 1–6.
Hüppi PS, Schuknecht B, Boesch C, Bossi E, Felblinger J, Fusch C, Herschkowitz N 1996 Structural and neurobehavioral delay in postnatal brain development of preterm infants. Pediatr Res 39: 895–901.
Cady EB, Penrice J, Amess PN, Lorek A, Wylezinska M, Aldridge RF, Franconi F, Wyatt JS, Reynolds EOR 1996 Lactate, N-acetylaspartate, choline and creatine concentrations, and spin-spin relaxation in thalamic and occipito-parietal regions of developing human brain. Magn Reson Med 36: 878–886.
Lu D, Pavlakis SG, Frank Y, Bakshi S, Pahwa S, Gould RJ, Sison C, Hsu C, Lesser M, Hoberman M, Barnett T, Hyman RA 1996 Proton MR spectroscopy of the basal ganglia in healthy children and children with AIDS. Radiology 199: 423–428.
Holshouser BA, Ashwal S, Luh GY, Shu S, Kahlon S, Auld KL, Tomasi LG, Perkin RM, Hinshaw DB 1997 Proton MR spectroscopy after acute central nervous system injury: : outcome prediction in neonates, infants, and children. Radiology 202: 487–496.
Pouwels PJW, Frahm J 1998 Regional metabolite concentrations in human brain as determined by quantitative localized proton MRS. Magn Reson Med 39: 53–60.
Frahm J, Hanefeld F 1997 Localized proton magnetic resonance spectroscopy of brain disorders in childhood. In: Bachelard HS (ed) Advances in Neurochemistry, Vol. 8. Plenum, New York, 329–402.
Frahm J, Michaelis T, Merboldt KD, Bruhn H, Gyngell ML, Hänicke W 1990 Improvements in localized 1H NMR spectroscopy of human brain. J Magn Reson 90: 464–473.
Klose U 1990 In vivo proton spectroscopy in presence of eddy currents. Magn Reson Med 14: 26–30.
Provencher SW 1993 Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30: 672–679.
Michaelis T, Merboldt KD, Bruhn H, Hänicke W, Frahm J 1993 Absolute concentrations of metabolites in the adult human brain in vivo: : quantification of localized proton MR spectra. Radiology 187: 219–227.
Pouwels PJW, Frahm J 1997 Differential distribution of NAA and NAAG in human brain as determined by quantitative localized proton MRS. NMR Biomed 10: 73–78.
Pouwels PJW, Kruse B, Hanefeld F, Frahm J 1997 Age dependence of human cerebral metabolites in gray matter, white matter, and basal ganglia as determined by quantitative localized proton MRS. Proceedings of the 5th annual meeting of the International Society for Magnetic Resonance in Medicine (ISMRM), Vancouver, 482
Birken DL, Oldendorf WH 1989 N-Acetyl- L -aspartic acid: : a literature review of a compound prominent in 1H NMR spectroscopic studies of brain. Neurosci Biobehav Rev 13: 23–31.
Moffett JR, Namboodiri MAA, Neale JH 1993 Enhanced carbodiimide fixation for immunohistochemistry: application to the comparative distributions of N-acetylaspartylglutamate and N-acetylaspartate immunoreactivities in rat brain. J Histochem Cytochem 41: 559–570.
Moffett JR, Namboodiri MAA 1995 Differential distribution of N-acetylaspartylglutamate and N-acetylaspartate immunoreactivities in rat forebrain. J Neurocytol 24: 409–433.
Kelly JP, Dodd J 1991 Anatomical organization of the nervous system. In: Kandel ER, Schwartz JH, Jessell TM (eds) Principles of Neural Science, 3rd Ed. Elsevier, New York, 273–282.
Miyake M, Kakimoto Y 1981 Developmental changes of N-acetyl- L -aspartic acid, N-acetyl-α-aspartylglutamic acid and β-citryl- L -glutamic acid in different brain regions and spinal cords of rat and guinea pig. J Neurochem 37: 1064–1067.
Blakely RD, Coyle JT 1988 Neurobiology of N-acetylaspartylglutamate. In: Smythies JR, Bradley RJ (eds) International review of neurobiology, Vol. 30. Academic Press, San Diego, 39–100.
Buchli R, Martin E, Boesiger P, Rumpel H 1994 Developmental changes of phosphorus metabolite concentrations in the human brain: : a 31P magnetic resonance spectroscopy study in vivo. Pediatr Res 35: 431–435.
Requardt M 1995 In vivo31P-NMR-Spektroskopie der Kreatinkinasereaktion am Skelettmuskel und Gehirn des Menschen. Dissertation, Universität Göttingen, Germany, 69–73.
Buchli R, Duc CO, Martin E, Boesiger P 1994 Assessment of absolute metabolite concentrations in human tissue by 31P MRS in vivo. Magn Reson Med 32: 447–452.
Holtzman D, Mulkern R, Tsuji M, Cook C, Meyers R 1996 Phosphocreatine and creatine kinase in piglet cerebral gray and white matter in situ. Dev Neurosci 18: 535–541.
Dingledine R, McBain CJ 1994 Excitatory amino acid transmitters. In: Siegel GJ, Agranoff BW, Albers RW, Molinoff PB (eds) Basic Neurochemistry, 5th Ed. Raven Press, New York, 367–387.
Sturman JA 1993 Taurine in development. Physiol Rev 73: 119–147.
Nakada T, Kwee IL, Igarashi H 1994 Brain maturation and high-energy phosphate diffusivity: alteration in cytosolic microenvironment and effective viscosity. Dev Brain Res 80: 121–126.
DeLorey TM, Olsen RW 1994 GABA and glycine. In: Siegel GJ, Agranoff BW, Albers RW, Molinoff PB (eds) Basic Neurochemistry, 5th Ed. Raven Press, New York, 389–399.
Clarke DD, Sokoloff L 1994 Circulation and energy metabolism of the brain. In: Siegel GJ, Agranoff BW, Albers RW, Molinoff PB (eds) Basic Neurochemistry, 5th Ed. Raven Press, New York, 645–680.
Hallgren B, Sourander P 1958 The effect of age on the non-haemin iron in the human brain. J Neurochem 3: 41–51.
Aoki S, Okada Y, Nishimura K, Barkovich AJ, Kjos BO, Brasch RC, Norman D 1989 Normal deposition of brain iron in childhood and adolescence: : MR imaging at 1. Radiology 172: 381–385.
Acknowledgements
The authors thank Dr. Stephen Provencher for continuing support in the use of LCModel and Xiangling Mao for developing data processing software.
Author information
Authors and Affiliations
Additional information
P.J.W. Pouwels was supported by a fellowship of the European Community (ERBCHBGCT 940722).
Rights and permissions
About this article
Cite this article
Pouwels, P., Brockmann, K., Kruse, B. et al. Regional Age Dependence of Human Brain Metabolites from Infancy to Adulthood as Detected by Quantitative Localized Proton MRS. Pediatr Res 46, 474 (1999). https://doi.org/10.1203/00006450-199910000-00019
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-199910000-00019
This article is cited by
-
Microstructural and Metabolic Changes in Normal Aging Human Brain Studied with Combined Whole-Brain MR Spectroscopic Imaging and Quantitative MR Imaging
Clinical Neuroradiology (2023)
-
Magnetic resonance spectroscopy brain metabolites at term and 3-year neurodevelopmental outcomes in very preterm infants
Pediatric Research (2022)
-
Brain proton magnetic resonance spectroscopy and neurodevelopment after preterm birth: a systematic review
Pediatric Research (2022)
-
Altered brain metabolite concentration and delayed neurodevelopment in preterm neonates
Pediatric Research (2022)
-
Edited magnetic resonance spectroscopy in the neonatal brain
Neuroradiology (2022)
