Of all neurotransmitter systems, the glutamatergic neurotransmission has been suggested to be involved in the pathogenesis of age-related neurodegenerative diseases.¹ Glx [summation of glutamate (Glu) and glutamine (Gln)] has an interesting role in aging as it could be used as a central measure for glutamatergic neurotransmission by assessing the entire brain pool of Glu and Gln. Glu is the most important excitatory neurotransmitter in the brain, and Gln is the precursor and reaction product of Glu in the Glu/Gln cycle. The anterior cingulate cortex (ACC) has recently become a focus for aging research because of its implicated role in attention and mood regulation. A functional MRI study in older adults even demonstrated an increase in blood oxygen level-dependent signal in the ACC during the Stroop task, suggesting compensation.² Apart from the ACC, the posterior cingulate cortex (PCC) has always been of focus in aging research as it is a highly connected and metabolically active brain region. The PCC is also believed to be closely associated with Alzheimer’s disease (AD). In this study, we investigated the changes in glutamatergic neurotransmission during aging by quantifying Glx in the ACC and PCC of a local Chinese cohort using quantitative proton magnetic resonance spectroscopy.30 cognitively normal (Mini-mental State Examination≥28) subjects (mean = 49.9±18.3 years, age range 22-82 years) underwent MR scan using 3.0T Achieva TX scanner, Philips Healthcare. PRESS (TR/TE = 2000/39 ms) was used as volume selection method with single voxels of 2 x 2 x 2 cm³ placed in the ACC and PCC. Glx was measured and quantified using internal water as reference by QUEST in jMRUI (4.0) (Figure 1). Cerebrospinal fluid (CSF) normalization, water content correction for grey matter, white matter and CSF, and correction factor for T1 relaxation were also implemented. Pearson correlation coefficient (r) was calculated to assess the correlation between absolute Glx concentration ([Glx]_abs) and age in the ACC and PCC. Two-sample t-test was used to investigate any regional differences in [Glx]_abs between ACC and PCC. Subjects were divided into young-age group (22-50 years, n=15) and old-age group (51-82 years, n=15) for further investigation of group differences in [Glx]_abs in both ACC and PCC. SPSS version 20.0 was used for statistical analysis and level of significance was set at 0.05.Figure 2 shows scatter plots between age and [Glx]_abs in the ACC (9.28 ± 2.55 mM) and PCC (7.47 ± 1.03 mM). [Glx]_abs showed a significant positive correlation with age in both the ACC (r = 0.403; p = 0.027) and PCC (r = 0.404; p = 0.027). Further statistical analysis showed that overall [Glx]_abs in the ACC was significantly higher (p = 0.001) than that of PCC within the 30 participants. In addition, only the ACC showed significantly higher [Glx]_abs (p = 0.033) in the old-age group compared (10.26 ± 2.30 mM) with young-age group (8.31 ± 2.47 mM), whereas no significant difference was shown in the PCC.

Age-related increase of [Glx]_abs in ACC and PCC

The significant age-related increases of [Glx]_abs in the ACC and PCC might indicate age-related alterations in the glutamatergic neurotransmission. This alteration might further imply disruptions between glial cells and neurons in the Glu/Gln cycle, which is thought to be tightly coupled to maintain proper regulation of glutamatergic neurotransmission under normal healthy conditions.^₃ Although the age-related increase in [Glx]_abs might be due to increase(s) in either Glu, or Gln, or both, it is important to note that excessive Glu at the synaptic cleft is excitotoxic, which has been proposed to be a plausible mechanism leading to AD. Further investigation in glutamatergic neurotransmission through monitoring the age-related changes in ratio of Glu:Gln might provide clues on understanding the mechanism of the “aging brain”.

Higher [Glx]_abs in ACC

The significantly higher overall [Glx]_abs in the ACC compared with PCC could possibly be attributed to the distribution of glutamatergic neurons in the human brain. It has been reported that abundant glutamatergic neurons are mainly distributed in the forebrain.²

Only ACC shows higher [Glx]_abs in older adults

Interestingly, in the young-age group versus old-age group analysis, only the ACC showed significant higher [Glx]_abs in the old-age group. This finding suggested a pattern of metabolic changes specific to the ACC, but not the PCC, which might support the functional compensatory recruitment theory shown in previous studies.⁴

ACC has a high-lighted role in the aging brain, which might help to understand the pathophysiological changes in age-related neurodegenerative diseases.