Proton magnetic resonance spectroscopy was performed at 3 T using the echo time-averaged point-resolved spectroscopy method to determine the effects of age, gender and brain region on glutamate (Glu) concentrations in the healthy human brain. Thirty healthy men and 20 healthy women aged between 21 and 71 years were studied. Significant regional variations of Glu concentrations were observed. Glu concentration in the gray matter (GM) was approximately 25% higher than that in the white matter. Significant age-dependent decreases in Glu concentrations were observed in the basal ganglia (r=-0.75, P<.001) and parietal GM (r=-0.66, P<.001) of men but not those of women. Our findings demonstrate regional variations of Glu concentrations and suggest that the male brain may be more vulnerable to aging than the female brain. Our results also highlight the importance of brain region, age and gender matching in clinical studies.
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"Our Glu findings are in contrast with the literature in the general population, which suggests an age-related decline in Glu or no age-related change (Marsman et al. 2013; Sailasuta et al. 2008). An MRS study in the general population showed that Gln tended to increase with age (Kaiser et al. 2005), whereas our findings in plasma were in the opposite direction. "
[Show abstract][Hide abstract] ABSTRACT: Patients with 22q11 deletion syndrome (22q11DS) have a high prevalence of intellectual disabilities and psychiatric disorders, including psychosis. Haplo-insufficiency of genes in the deleted region may offer a partial explanation for the increased vulnerability for psychosis and intellectual disability. One gene of particular interest is the gene coding for proline dehydrogenase (PRODH), an enzyme responsible for the conversion of proline into glutamate.
Because abnormalities in glutamatergic signaling are thought to be responsible for cognition and psychosis in the general population, we hypothesized that PRODH haplo-insufficiency may underlie some of the cognitive and psychotic features seen in 22q11DS.
In this explorative study, we investigated the relation between plasma proline, glutamate, and glutamine and age, intelligence, and psychosis in 64 adults with 22q11DS.
Hyperprolinemia was found in 31.3 % of subjects with 22q11DS. A relation between glutamine, glutamate, proline, and presence of psychosis was not observed. Regression analysis revealed a positive relation between plasma glutamate and age, a positive relation of glutamate with antipsychotic drugs, a relation of glutamine and gender, and a positive relation of glutamine and mood stabilizing drugs, and a negative relation of the ratio glutamine/glutamate and age. The group with relatively lower IQ had higher glutamate levels compared to the group with relatively higher IQ.
Our results suggest that 22q11DS is accompanied by abnormalities in glutamatergic metabolism. Future longitudinal studies are needed to further investigate the glutamatergic system in 22q11DS and how this affects the development of cognitive problems and psychopathology.
Full-text · Article · Jun 2015 · Psychopharmacology
"Activated microglia were shown to release increased levels of glutamate (Noda et al., 1999; Barger et al., 2007; Takaki et al., 2012). However, several studies have shown lower glutamate concentration in older subjects when compared to younger individuals (Kaiser et al., 2005; Sailasuta et al., 2008; Chang et al., 2009) and an age-dependent decline of glutamate release in mice (Minkeviciene et al., 2008). This finding is in line with the reduced glutamate levels we obtained in aged cell cultures. "
[Show abstract][Hide abstract] ABSTRACT: Age-related neurodegenerative diseases have been associated with chronic neuroinflammation and microglia activation. However, cumulative evidence supports that inflammation only occurs at an early stage once microglia change the endogenous characteristics with ageing and switch to irresponsive/senescent and dystrophic phenotypes with disease progression. Thus, it will be important to have the means to assess the role of reactive and aged microglia when studying advanced brain neurodegeneration processes and age-associated related disorders. Yet, most studies are done with microglia from neonates since there are no adequate means to isolate degenerating microglia for experimentation. Indeed, only a few studies report microglia isolation from aged animals, using either short-term cultures or high concentrations of mitogens in the medium, which trigger microglia reactivity. The purpose of this study was to develop an experimental process to naturally age microglia after isolation from neonatal mice and to characterize the cultured cells at 2 days in vitro (DIV), 10 DIV and 16 DIV. We found that 2 DIV (young) microglia had predominant amoeboid morphology and markers of stressed/reactive phenotype. In contrast, 16 DIV (aged) microglia evidenced ramified morphology and increased metalloproteinase (MMP)-2 activation, as well as reduced MMP-9, glutamate release and nuclear factor kappa-B activation, in parallel with decreased expression of Toll-like receptor (TLR)-2 and TLR-4, capacity to migrate and phagocytose. These findings together with the reduced expression of microRNA (miR)-124, and miR-155, decreased autophagy, enhanced senescence associated beta-galactosidase activity and elevated miR-146a expression, are suggestive that 16 DIV cells mainly correspond to irresponsive/senescent microglia. Data indicate that the model represent an opportunity to understand and control microglial aging, as well as to explore strategies to recover microglia surveillance function.
Full-text · Article · Jun 2014 · Frontiers in Cellular Neuroscience
"Previous 1 H MRS studies have detected age-related metabolite concentration changes in healthy adult subjects (Brooks et al. 2001; Sailasuta et al. 2008; Chang et al. 2009) although the literature documenting metabolite changes throughout adolescence is sparse. One 1 H MRS study tracked NAA levels throughout childhood and adolescence demonstrating a rise in gray matter NAA/Cho ratios with a maximum level reached at approximately 10 years of age and a decline thereafter (Horska et al. 2002). "
[Show abstract][Hide abstract] ABSTRACT: Converging evidence from neuroimaging and neuropsychological studies indicates that heavy marijuana use is associated with cingulate dysfunction. However, there has been limited human data documenting in vivo biochemical brain changes after chronic marijuana exposure. Previous proton magnetic resonance spectroscopy studies have demonstrated reduced basal ganglia glutamate and dorsolateral prefrontal cortex N-acetyl aspartate levels in adult chronic marijuana users. Similar studies have not been reported in adolescent populations. The present study used proton magnetic resonance spectroscopy to determine whether reductions in glutamate, N-acetyl aspartate and/or other proton metabolite concentrations would be found in the anterior cingulate cortex (ACC) of adolescent marijuana users compared with non-using controls. Adolescent marijuana users (N=17; average age 17.8 years) and similarly aged healthy control subjects (N=17; average age 16.2 years) were scanned using a Siemens 3T Trio MRI system. Proton magnetic resonance spectroscopy data were acquired from a 22.5 mL voxel positioned bilaterally within the ACC. Spectra were fitted using commercial software and all metabolite integrals were normalized to the scaled unsuppressed water integral. Analysis of variance and analysis of covariance were performed to compare between-group metabolite levels. The marijuana-using cohort showed statistically significant reductions in anterior cingulate glutamate (-15%, p<0.01), N-acetyl aspartate (-13%, p=0.02), total creatine (-10%, p<0.01) and myo-inositol (-10%, p=0.03). Within-voxel tissue-type segmentation did not reveal any significant differences in gray/white matter or cerebrospinal fluid content between the two groups. The reduced glutamate and N-acetyl aspartate levels in the adolescent marijuana-using cohort are consistent with precedent human (1)H MRS data, and likely reflect an alteration of anterior cingulate glutamatergic neurotransmission and neuronal integrity within these individuals. The reduced total creatine and myo-inositol levels observed in these subjects might infer altered ACC energetic status and glial metabolism, respectively. These results expand on previous functional MRI data reporting altered cingulate function in individuals with marijuana-abuse.