Detection Of Brain GABA Levels In Postmenopausal Women With Mild-to-moderate Depression By Proton MR Pectroscopy

The postmenopausal women are in a particular physiological periods, including the function loss of ovarian and lower estrogen levels, which could lead to physical and mental and behavioral abnormalities, named postmenopausal syndrome (ICD-10: N95.1). The symptom of depressive is common among postmenopausal women with postmenopausal women, and some of them even to fulfill the criteria of depression. In fact, depression could obviously influence the physical and mental health, communication and daily work of such kind of patients. However, most patients are presented with mild-to-moderate depression and easily to be ignored. With the increase of human life extended, postmenopausal women would take a long period after menopause till the end of life. Therefore, more and more attention is paid to the postmenopausal depression. Previous studies indicated that the low levels of estrogen were related to depression. However, the therapy effects were inconsistent about estrogen or estrogen combined with progesterone. Similar with premenstrual dysphoric disorder, depression in postmenopausal women is also a multi-factors disease. Therefore, further study of pathophysiology of depression could provide the accurate and reliable basis for diagnosis and therapy.As the main inhibitory neurotransmitter in the central nervous system (CNS), Gamma-aminobutyric acid (GABA) is closely related to the brain function, especially the mood regulation and recognition. It is increasingly being recognized that alterations of the GABAergic system are implicated in the pathophysiology of depression. Related studies have suggested the glutamic acid decarboxylase (GAD) and the function of GABA receptor are regulated by estrogen and progesterone and its metabolites. Many studies have detected changes in GABA-inhibitory function during the menstrual cycle, pregnancy and postpartum. However, there is little information on cerebral GABA levels in postmenopausal women with depression.Proton magnetic resonance spectroscopy(1H-MRS) methods permit researchers to noninvasively quantify brain metabolites. With the development of'H-MRS, the detection and quantity of routine metabolites is more and more accurate, such as N-acetyl-aspartate (NAA), myo-inositol (ml), choline (Cho), total creatine (TCr) and lactate (Lac).'H-MRS technique has been widely used to many CNS diseases. However, detection of GABA using the conventional 1H-MRS is limited due to its relatively low concentration and the spectral overlap of signals from other major metabolites. Now an advanced MRS method, MEGA-PRESS has been used to detect GABA levels in the healthy brain and various psychiatric diseases. Herein, we explore the cerebral GABA levels in postmenopausal women using the edited MRS technique MEGA-PRESS on 3.0T MR scanner. The present study would detect the GABA levels on the VOI of ACC/mPFC and PCC between depression group and healthy controls group. As the main exciting neurotransmitter in the central nervous system (CNS), glutamate is closely connected to the mood disorders. Just like GABA, routine 1H-MRS couldn't detect the glutamate signal due to the overlapping of resonance peaks of Glu and Gln. Here, we would use the Asymmetric Point Resolved Spectroscopy (A-PRESS) sequence separating glutamate from glutamine.There are three parts for the study:Part ?. The reproducibility study of MEGA-PRESS technique in vivo detection of brain GABAconcentrationsObjective:Using MEGA-PRESS editing sequence to explore brain GABA levels in ACC/mPFC and PCC of healthy volunteers, and investigate the reproducibility of relative quantification and absolute quantification.Material and Methods:8 right-handed healthy volunteers (1male,7women; mean age:4536±10.7 y, age range:31-56 y) participated in this study. MRI scanner is 3.0T Philips (Achieva, TX, Best, The Netherlands), equipped with an eight-channel phased-array head coil. First, a T1-weighted 3D TFE scan was acquired for MRS voxel placement and tissue segmentation. Spectra were recorded from the ACC/mPFC and PCC by MEGA-PRESS sequence. A reference water spectrum was also collected from the same voxel without water suppression, which was later used for absolute quantification. Eight subjects were scanned at least twice. Four of them were scanned three times within three weeks. Each voxel in the 3D T1-weighted structural images was segmented using FSL package (Oxford University, Oxford, UK). Post-processing of the MRS data was carried out using "Gannet" automatically. GABA+levels were quantified by relative quantification (GABA+/Cr) and absolute quantification (GABA+). Differences of GABA+levels from inter-individual of volunteers were tested using repeated measures analysis of variance.Results:GABA+difference spectra were successfully quantified from all eight volunteers. There were no differences of GABA+levels between groups of volunteers. The four volunteers for three times detection (ACC/mPFC:GABA+/Cr, p= 0.13; GABA+, p=0.74; PCC:GABA+/Cr, p=0.10; GABA+, p=0.22); the eight volunteers for twice (ACC/mPFC:GABA+/Cr, p=0.32; GABA+, p=0.43; PCC: GABA+/Cr,p= 0.19; GABA+,p=0.27).Conclusion:The MEGA-PRESS technique was stable to resolve and detect GABA signals in human brain.Part ?. The GABA+concentrations in postmenopausal women with mild-to-moderate depressionObjective:To explore in vivo GABA levels in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and posterior-cingulate cortex (PCC) of postmenopausal women with depression using magnetic resonance spectroscopy (1H-MRS).Materials and Methods:Nineteen postmenopausal women (53.9±2.6y) with depression and twenty-two healthy controls (52.8±1.9y) were enrolled in the study. All the participants were natural menopause at least 2-8 years. The symptomatic severity of depression was assessed by 17-item Hamilton Depression Scale and the 14-item Hamilton Anxiety Scale was also performed simultaneously. All subjects underwent 1H-MRS of the ACC/mPFC and PCC using the "MEGA Point Resolved Spectroscopy Sequence" (MEGA-PRESS) technique. First, a T1-weighted 3D TFE scan was acquired for MRS voxel placement and tissue segmentation. Spectra were recorded from the ACC/mPFC and PCC by MEGA-PRESS sequence. A reference water spectrum was also collected from the same voxel without water suppression, which was later used for absolute quantification. Quantification of MRS data was performed using Gannet program. Differences of GABA+levels from patients and controls were tested using one-way analysis of variance. Spearman correlation coefficients were used to evaluate the linear associations between GABA+levels and HAMD scores, as well as estrogen levels.Results:Significantly lower GABA+levels were detected in the ACC/mPFC of postmenopausal women with depression compared to healthy controls (p=0.011). No significant correlations were found between 17-HAMD/14-HAMA and GABA+ levels, either in ACC/mPFC (p=0.38; r=0.22/p=0.82; r=0.06) or PCC (p=0.77; r=0.07/p=0.32; r=0.19) in the patients; there is also no significant correlation between GABA+levels and estrogen levels in patients group (ACC/mPFC:p=0.88, r=0.04; PCC:p=0.96,r=-0.01).Conclusion:Significantly lower GABA+levels were found in the ACC/mPFC of postmenopausal women with depression, suggesting that the dysfunction of the GABAergic system may also be involved in the pathogenesis of depression in postmenopausal women.Part ?. The Glutamate levels in postmenopausal women with mild-to-moderate depressionObjective:To explore in vivo Glutamate levels in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and posterior-cingulate cortex (PCC) of postmenopausal women with depression using magnetic resonance spectroscopy (1H-MRS).Materials and Methods:Eighteen postmenopausal women (53.9±2.6y) with depression and twenty-two healthy controls (52.7±2.3y) were enrolled in the study. All the participants were natural menopause at least 2-8 years. The symptomatic severity of depression was assessed by 17-item Hamilton Depression Scale and the 14-item Hamilton Anxiety Scale was also performed simultaneously. All subjects underwent'H-MRS of the ACC/mPFC and PCC using the "Aymmetric Point Resolved Spectroscopy Sequence" (A-PRESS) technique. First, a T1-weighted 3D TFE scan was acquired for MRS voxel placement and tissue segmentation. Spectra were recorded from the ACC/mPFC and PCC by A-PRESS sequence. Quantification of MRS data was performed using QUEST program. Differences of Glutamate levels from patients and controls were tested using one-way analysis of variance. Spearman correlation coefficients were used to evaluate the linear associations between Glutamate levels and HAMD/HAMA scores.Results:Significantly higher Glutamate levels were detected in the ACC/mPFC of postmenopausal women with depression (0.97±0.07) compared to healthy controls (0.92±0.06) (p=0.046). The glutamate levels were also higher in patients group (0.85±0.06) compared to healthy controls group (0.84±0.03), but no significant. No significant correlations were found between 17-HAMD/14-HAMA and Glutamate levels, either in ACC/mPFC or PCC (p>0.05 in all).Conclusion:Significantly higher Glutamate levels were found in the ACC/mPFC of postmenopausal women with depression, suggesting that the dysfunction of the Glutamate-ergic system may also be involved in the pathogenesis of depression in postmenopausal women.