Original contributionsRegional variations and the effects of age and gender on glutamate concentrations in the human brain☆
Introduction
Glutamate (Glu) is one of the most prevalent neurotransmitters in the brain and the primary excitatory neurotransmitter in the mammalian central nervous system (CNS). In the brain, Glu and glutamine (Gln) are compartmentalized primarily within the neurons and glia (astrocytes), respectively. Transient increases in extracellular Glu occur normally when glutamatergic neurons depolarize, but the extracellular Glu is typically taken up quickly by astrocytes. However, toxicity to brain cells can occur in pathological states during prolonged extracellular exposure to high Glu concentrations [1]. The neurotoxicity of Glu has been implicated in a wide range of neurodegenerative diseases, including multiple sclerosis (MS) [2], amyotrophic lateral sclerosis [3], Alzheimer's disease (AD) [4], [5], [6] and schizophrenia [7]. Glu also plays key roles in pathological processes that occur as a result of CNS insults, such as stroke, head trauma and spinal injuries [8].
Major brain chemicals that are easily detectable with both short (30–45 ms) and long (135–270 ms) echo times (TEs) in conventional single-voxel proton magnetic resonance spectroscopy (MRS) include N-acetylaspartate (NAA; 2.02 ppm), total creatine (Cr; 3.03 ppm), choline (Cho)-containing compounds (3.22 ppm) and myo-inositol (mI; 3.7 ppm). At short TEs, the overlapping resonances of Glu plus Gln are also readily measured as total Glu+Gln (Glx). Glx concentrations appear to be abnormal in various brain disorders; for instance, increases in Glx levels have been reported in patients with epilepsy [9] and hepatic encephalopathy [10], while decreases in Glx have been found in those with AD [5], obsessive–compulsive disorder [11] and antiretroviral-naive HIV [12]. Unfortunately, Glx does not measure changes in Glu/Gln stasis and is less likely to be an adequate marker for changes in intracellular conditions that may precede or accompany conditions of Glu excitotoxicity. Therefore, measurement of Glu without contamination of Gln and the aspartyl group of NAA resonances would be very important for assessing excitotoxicity in brain disorders. However, direct detection of Glu using proton MRS in the brain is difficult at magnetic field strengths below 4 T due to the strong coupling of Glu, Gln and the aspartyl moiety of NAA resonances.
Recently, a method for measuring uncontaminated brain Glu concentrations using TE-averaged point-resolved spectroscopy (PRESS) has been applied successfully in MS [13] and AD [14] patients. However, it is unclear how Glu concentrations vary in different brain regions and whether age and gender affect the Glu concentration. The present study aimed to apply the TE-averaged PRESS method to determine if there are regional differences in Glu concentrations among four brain regions: frontal white matter (FWM); frontal gray matter (FGM); parietal GM (PGM); and basal ganglia (BG). In addition, we aimed to determine whether Glu concentrations vary with gender and age. Concentrations of other major brain metabolites (NAA, Cr and Cho), as determined by the TE-averaged PRESS method, are reported as well.
Section snippets
Subjects
Fifty healthy participants (30 men and 20 women) were recruited from the local community. The study participants were between 21 and 71 years old (mean±S.D.=40.4±14.9 years). Of this group, 16 participants were aged between 20 and 30 years, 11 were aged between 30 and 40 years, 6 were aged between 40 and 50 years, 11 were aged between 50 and 60 years and 6 were aged between 60 and 71 years. The men and women had 14.6±2.4 and 15.9±2.3 years of education, respectively. All subjects were in good
Regional variations of CSF content in the brain in relation to age
The ratios of CSF and brain water content in each voxel were calculated from the biexponential fitting of the T2 decay curve. Significant positive correlations of CSF partial volume and age were observed in the PGM (r=0.502, P<.001), BG (r=0.356, P=.01) and FGM (r=0.566, P<.001). However, only a trend for correlation between age and CSF was observed in the FWM (r=0.262, P=.09).
Precision and reproducibility of Glu measurements
Fifteen participants were scanned with both conventional single-voxel PRESS at a TE of 30 ms and TE-averaged PRESS to
Discussion
The major findings of this study were regional variations of Glu concentrations (FGM>PGM>FWM>BG) and age-related decline in Glu concentrations, particularly in the BG and PGM of men, with fewer changes in women.
Acknowledgments
This study was supported by the National Institutes of Health (1K25DA021112 for N.S., 5K24DA016170 for L.C. and 5K02DA016991 for T.E.).
We thank Drs. Jimmy Efird and Jim Davis for their guidance on the statistical analyses of the data. We also thank L. Girton, R. Yakupov and Dr. K. Yue for their assistance in the MRS data acquisition as well as Dr. Christine Cloak, D. Ramones, K. Taketa, T. Chahil and T. Wu for their assistance in subject recruitment and evaluations.
References (42)
- et al.
Abnormal glutamic acid metabolism in multiple sclerosis
J Neurol Sci
(1980) - et al.
Decrease in caudate glutamatergic concentrations in pediatric obsessive–compulsive disorder patients taking paroxetine
J Am Acad Child Adolesc Psychiatry
(2000) - et al.
Relationships among brain metabolites, cognitive function, and viral loads in antiretroviral-naive HIV patients
Neuroimage
(2002) - et al.
Effects of gender and region on proton MRS of normal human brain
Magn Reson Imaging
(1999) - et al.
Cerebral volumes and spectroscopic proton metabolites on MR: is sex important?
Magn Reson Imaging
(1997) - et al.
Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T
Neurobiol Aging
(2005) - et al.
Glutamatergic neurotransmission in aging: a critical perspective
Mech Ageing Dev
(2001) - et al.
Beyond the role of glutamate as a neurotransmitter
Nat Rev Neurosci
(2002) - et al.
1H-MRS evidence of neurodegeneration and excess glutamate+glutamine in ALS medulla
Neurology
(1999) - et al.
Glutamatergic neurotransmission in Alzheimer's disease
Biochem Soc Trans
(1990)
Decreased glutamate+glutamine in Alzheimer's disease detected in vivo with (1)H-MRS at 0.5 T
Neurology
1H-MRS evaluation of metabolism in Alzheimer's disease and vascular dementia
Neurol Res
Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers
Am J Psychiatry
Neuronal apoptosis after CNS injury: the roles of glutamate and calcium
J Neurotrauma
Increased thalamus levels of glutamate and glutamine (Glx) in patients with idiopathic generalised epilepsy
J Neurol Neurosurg Psychiatry
Adding another spectral dimension to 1H magnetic resonance spectroscopy of hepatic encephalopathy
J Magn Reson Imaging
Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T
Brain
1H MR spectroscopy using TE averaged PRESS: a more sensitive technique to detect neurodegeneration associated with Alzheimer's disease
Magn Reson Med
Three-dimensional magnetization-prepared rapid gradient-echo imaging (3D MP RAGE)
Magn Reson Med
Measurement of brain glutamate using TE-averaged PRESS at 3T
Magn Reson Med
Estimation of metabolite concentrations from localized in vivo proton NMR spectra
Magn Reson Med
Cited by (92)
Stable isotope tracing reveals disturbed cellular energy and glutamate metabolism in hippocampal slices of aged male mice
2023, Neurochemistry InternationalTreatment resistance NMDA receptor pathway polygenic score is associated with brain glutamate in schizophrenia
2023, Schizophrenia ResearchOn the relationship between GABA+ and glutamate across the brain
2022, NeuroImage
- ☆
Parts of this study were presented at the 14th ISMRM Scientific Meeting in Seattle (2006).