Glutamate-glutamine and GABA in brain of normal aged and patients with cognitive impairment

Huang, Dandan; Liú, Dan; Yin, Jianzhong; Qian, Tianyi; Shrestha, Susan; Ni, Hongbo

doi:10.1007/s00330-016-4669-8

Cited by 97 publications

(90 citation statements)

References 36 publications

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“…Cognitive performance was strongly correlated with frontal GABA+ concentrations, even after accounting for age, the fraction of cerebral spinal fluid (CSF) in the MRS voxel (a coarse measure of brain atrophy) and behavioral factors such as education or age related normative performance. This is consistent with prior animal work showing age-related declines in GABA+ (4) and a cross-sectional study observing lower GABA+ concentrations in the right hippocampus in healthy elderly controls compared to young controls, though no differences were observed in the anterior cingulate (5). …”

Section: Introductionsupporting

confidence: 92%

Impact of tissue correction strategy on GABA-edited MRS findings

et al. 2017

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Tissue composition impacts the interpretation of magnetic resonance spectroscopy metabolite quantification. The goal of applying tissue correction is to decrease the dependency of metabolite concentrations on the underlying voxel tissue composition. Tissue correction strategies have different underlying assumptions to account for different aspects of the voxel tissue fraction. The most common tissue correction is the CSF-correction that aims to account for the cerebrospinal fluid (CSF) fraction in the voxel, in which it is assumed there are no metabolites. More recently, the α-correction was introduced to account for the different concentrations of GABA+ in gray matter and white matter. In this paper, we show that the selected tissue correction strategy can alter the interpretation of results using data from a healthy aging cohort with GABA+ measurements in a frontal and posterior voxel. In a frontal voxel, we show an age-related decline in GABA+ when either no tissue correction (R2= 0.25, p < 0.001) or the CSF-correction is applied (R2= 0.08, p < 0.01). When applying the α-correction to the frontal voxel data, we find no relationship between age and GABA+ (R2= 0.02, p = 0.15). However, with the α-correction we still find that cognitive performance is correlated with GABA+ (R2= 0.11, p < 0.01). These data suggest that in healthy aging, while there is normal atrophy in the frontal voxel, GABA+ in the remaining tissue is not decreasing on average. This indicates that the selection of tissue correction can significantly impact the interpretation of MRS results.

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Section: Introductionsupporting

confidence: 92%

Impact of tissue correction strategy on GABA-edited MRS findings

et al. 2017

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“…Glutamate dehydrogenase (GDH) catalyzes the interconversion of glutamate to ␣ketoglutarate modulated by a redox sensitive site depending on NAD + /NADH levels [45]. Depletion of glutamate-glutamine and gamma-aminobutyric acid (GABA) were reported recently in normal aged human brains and cognitively impaired patients by magnetic resonance spectroscopy (MRS) [46]. These metabolites feed into ␣-ketoglutarate which functions as a critical NAD + /NADH-dependent substrate in the TCA cycle.…”

Section: Age-and Ad-associated Redox Pivot At Glutamate-α-ketoglutaramentioning

confidence: 99%

Global Metabolic Shifts in Age and Alzheimer’s Disease Mouse Brains Pivot at NAD+/NADH Redox Sites

Dong

Brewer

2019

JAD

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Age and Alzheimer's disease (AD) share some common features such as cognitive impairments, memory loss, metabolic disturbances, bioenergetic deficits, and inflammation. Yet little is known on how systematic shifts in metabolic networks depend on age and AD. In this work, we investigated the global metabolomic alterations in non-transgenic (NTg) and triple-transgenic (3xTg-AD) mouse brain hippocampus as a function of age by using untargeted Ultrahigh Performance Liquid Chromatography-tandem Mass Spectroscopy (UPLC-MS/MS). We observed common metabolic patterns with aging in both NTg and 3xTg-AD brains involved in energy-generating pathways, fatty acids oxidation, glutamate, and sphingolipid metabolism. We found age-related downregulation of metabolites from reactions in glycolysis that consumed ATP and in the TCA cycle, especially at NAD + /NADH-dependent redox sites, where age-and AD-associated limitations in the free NADH may alter reactions. Conversely, metabolites increased in glycolytic reactions in which ATP is produced. With age, inputs to the TCA cycle were increased including fatty acid ␤-oxidation and glutamine. Overall age-and AD-related changes were > 2-fold when comparing the declines of upstream metabolites of NAD + /NADH-dependent reactions to the increases of downstream metabolites (p = 10 −5 , n = 8 redox reactions). Inflammatory metabolites such as ceramides and sphingosine-1phosphate also increased with age. Age-related decreases in glutamate, GABA, and sphingolipid were seen which worsened with AD genetic load in 3xTg-AD brains, possibly contributing to synaptic, learning-and memory-related deficits. The data support the novel hypothesis that age-and AD-associated metabolic shifts respond to NAD(P) + /NAD(P)H redox-dependent reactions, which may contribute to decreased energetic capacity.

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“…One reason may be that the mean age of the participants was relatively higher compared with that of previous studies . According to a recent study, Glx shows a decreasing trend with aging, because elderly individuals develop decreases in neuronal density and metabolic activity 23) . To investigate appropriate regions for measuring Glx in depression, we will need to examine a younger group.…”

Section: Discussionmentioning

confidence: 99%

Physiologic and Characteristic Distributions of Glutamate/Glutamine in Patients with Major Depressive Disorder

Sakamoto

Nakamura

Sasaki

et al. 2018

J St. Marianna Univ

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Purpose Glutamate is the most abundant neurotransmitter in the brain, and proton magnetic resonance spectroscopy (MRS) allows quantification of glutamate-related metabolites (glutamate/glutamine complex; Glx). In previous findings, Glx has been lower in several brain regions of patients with major depressive disorder than in those of healthy controls. However, the physiologic and characteristic distribution of Glx in the same individual remains unclear. We attempted to clarify which brain regions reflect changes associated with depression. Material and method We measured Glx in 12 patients with depression and 12 healthy controls matched for age and sex in three brain regions (left amygdala, left anterior cingulate cortex, and left dorsolateral prefrontal cortex), and then compared the physiologic and characteristic distribution of Glx between the two groups. Results In comparisons of the distributions, Glx was significantly higher in the amygdala than in other regions. Glx tended to be lower among the patients than the controls, although no significant differences were present between the groups. We could not detect the changes expected from major depressive disorder (reduced Glx) in the amygdala, which regulates emotions and shows higher concentrations of Glx than other regions. Conclusion Previous studies have suggested that the concentration of Glx decreases with age, and this might have influenced our results regarding changes with major depressive disorder. In addition, we could not clarify whether medications affected the patient condition, because treatment for depression increased Glx in previous studies. Further MRS studies are needed to clarify Glx distributions in the specific diagnosis of depression.

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Glutamate-glutamine and GABA in brain of normal aged and patients with cognitive impairment

Abstract: • Glx and GABA levels may decrease simultaneously in normal aged. • Glx level may decrease predominantly in Alzheimer disease. • The balance in excitatory-inhibitory systems may be broken in AD. • Decreased Glx level may be helpful in early diagnosis of AD.

Cited by 97 publications

References 36 publications

Impact of tissue correction strategy on GABA-edited MRS findings

Impact of tissue correction strategy on GABA-edited MRS findings

Global Metabolic Shifts in Age and Alzheimer’s Disease Mouse Brains Pivot at NAD+/NADH Redox Sites

Physiologic and Characteristic Distributions of Glutamate/Glutamine in Patients with Major Depressive Disorder

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