Hormonal therapy is associated with localised changes in brain metabolites in post-menopausal women
Poster No:
934
Submission Type:
Abstract Submission
Authors:
Daniella Jones1, Zara Johal-Ayub2, Kathrin Cohen Kadosh1, Ines Violante3
Institutions:
1University of Surrey, Guildford, Surrey, 2Royal Holloway University, Egham, Surrey, 3King's College London, London, London
First Author:
Co-Author(s):
Introduction:
17β-Oestradiol (E2) is a crucial oestrogen steroid that regulates neural communication in the brain. Findings from animal studies suggest E2 levels decline during menopause may accelerate brain ageing in women. Hormone replacement therapy (HRT) is widely used to address hormonal imbalances and alleviate menopausal symptoms; however, its impact on brain health remains debated. While some studies suggest HRT reduces dementia risk, others report increased risks of stroke and cognitive decline.
The anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and inferior parietal lobule (IPL) are key regions implicated in cognitive processes and early Alzheimer's disease (AD) pathology.
In this study, we employed 1H-magnetic resonance spectroscopy (1H-MRS) to measure neurochemicals in the ACC, PCC, and IPL of two groups of post-menopausal women taking HRT or not.
The anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and inferior parietal lobule (IPL) are key regions implicated in cognitive processes and early Alzheimer's disease (AD) pathology.
In this study, we employed 1H-magnetic resonance spectroscopy (1H-MRS) to measure neurochemicals in the ACC, PCC, and IPL of two groups of post-menopausal women taking HRT or not.
Methods:
Sample: 71 postmenopausal women (50–65 years old), comprising 36 HRT users and 35 non-HRT users. Participants had no history of neurological or psychiatric disorders and were free from medical conditions influencing hormonal levels.
Oestradiol: Blood samples were used to measure free-circulating E2 levels.
MRI and MRS: 3T Siemens MRI used to acquire T1-weighted MP-RAGE (1-mm3 isotropic) and MRS using the MEGA-SPECIAL pulse sequence in the ACC, PCC, and IPL.
Data Analysis: MRS data were processed in MATLAB R2019b using the FID-A toolbox (Simpson et al., 2017) and LCModel (Version 6). Pre-processing included spectral registration to the time-domain signal for frequency and phase drift correction to improve spectral quality. To quantify absolute metabolite concentrations, average concentrations were referenced to cerebral water and corrected for tissue partial volume effects for all participants using the Gannet MRS pipeline (Edden et al., 2014). Only single metabolite values within 1.5 standard deviations below the mean, with a relative fit error of < 20 % Cramer-Rao lower bound (CRLB), SNR values > 4, and water linewidths < 0.1 ppm across all three voxel regions were retained for analysis.
Statistical Comparisons: Performed in R using Welch's t-tests for group differences, with p-values corrected for multiple comparisons using FDR method, and Cohen's d to assess the magnitude of group differences.
Oestradiol: Blood samples were used to measure free-circulating E2 levels.
MRI and MRS: 3T Siemens MRI used to acquire T1-weighted MP-RAGE (1-mm3 isotropic) and MRS using the MEGA-SPECIAL pulse sequence in the ACC, PCC, and IPL.
Data Analysis: MRS data were processed in MATLAB R2019b using the FID-A toolbox (Simpson et al., 2017) and LCModel (Version 6). Pre-processing included spectral registration to the time-domain signal for frequency and phase drift correction to improve spectral quality. To quantify absolute metabolite concentrations, average concentrations were referenced to cerebral water and corrected for tissue partial volume effects for all participants using the Gannet MRS pipeline (Edden et al., 2014). Only single metabolite values within 1.5 standard deviations below the mean, with a relative fit error of < 20 % Cramer-Rao lower bound (CRLB), SNR values > 4, and water linewidths < 0.1 ppm across all three voxel regions were retained for analysis.
Statistical Comparisons: Performed in R using Welch's t-tests for group differences, with p-values corrected for multiple comparisons using FDR method, and Cohen's d to assess the magnitude of group differences.
Results:
Hormonal Levels
HRT users exhibited significantly higher circulating E2 levels compared to non-HRT users, t(23.714)=7.392,p<.0001 (Fig.1).
Neurochemical Concentrations
HRT users demonstrated significantly elevated levels of N-acetyl-aspartate (NAA), aspartate (Asp), creatine (Cr), γ-aminobutyric acid (GABA), glutamate (Glu), glutathione (GSH), scyllo-inositol (Scyllo), myo-inositol (Ins), and phosphocreatine (PCr) concentrations in the ACC compared to non-HRT users (Fig. 2). Effect sizes for neurochemical differences in the ACC ranged from moderate to large (d=1.19 to 2.51), highlighting a substantial impact of HRT on metabolic activity in this region. These differences were not observed in the PCC or IPL.
HRT users exhibited significantly higher circulating E2 levels compared to non-HRT users, t(23.714)=7.392,p<.0001 (Fig.1).
Neurochemical Concentrations
HRT users demonstrated significantly elevated levels of N-acetyl-aspartate (NAA), aspartate (Asp), creatine (Cr), γ-aminobutyric acid (GABA), glutamate (Glu), glutathione (GSH), scyllo-inositol (Scyllo), myo-inositol (Ins), and phosphocreatine (PCr) concentrations in the ACC compared to non-HRT users (Fig. 2). Effect sizes for neurochemical differences in the ACC ranged from moderate to large (d=1.19 to 2.51), highlighting a substantial impact of HRT on metabolic activity in this region. These differences were not observed in the PCC or IPL.
Conclusions:
To our knowledge, despite the impact and importance of studying the effects of HRT on brain function post-menopause, this is the first study to conduct a multi-region investigation of the effects of HRT on brain chemistry.
Our results show significant localised neurochemical alterations associated with HRT use. In the ACC, HRT users exhibited elevated levels of multiple neurochemicals involved in neuronal integrity, neurotransmission, and antioxidant defence. No comparable neurochemical differences were observed in the PCC or IPL. This suggests that HRT's effects may be region-specific, potentially reflecting differences in oestrogen receptor density.
Given previous research suggesting the ACC's resilience to early neurodegenerative changes in AD, our findings suggest the importance of further investigation of HRT's neuroprotective potential.
Our results show significant localised neurochemical alterations associated with HRT use. In the ACC, HRT users exhibited elevated levels of multiple neurochemicals involved in neuronal integrity, neurotransmission, and antioxidant defence. No comparable neurochemical differences were observed in the PCC or IPL. This suggests that HRT's effects may be region-specific, potentially reflecting differences in oestrogen receptor density.
Given previous research suggesting the ACC's resilience to early neurodegenerative changes in AD, our findings suggest the importance of further investigation of HRT's neuroprotective potential.
Lifespan Development:
Aging 1
Novel Imaging Acquisition Methods:
MR Spectroscopy 2
Physiology, Metabolism and Neurotransmission:
Physiology, Metabolism and Neurotransmission Other
Keywords:
Aging
Magnetic Resonance Spectroscopy (MRS)
Neurological
Treatment
Other - Menopause; Hormones; Women's Health
1|2Indicates the priority used for review
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Provide references using APA citation style.
Provencher, S. W. (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn. Reson. Med., 30, 672–679.
Simpson, R., Devenyi, G. A., Jezzard, P., Hennessy, T. J., & Near, J. (2017). Advanced processing and simulation of MRS data using the FID appliance (FID-A)-An open source, MATLAB- based toolkit. Magnetic resonance in medicine, 77(1), 23–33.