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Exploring age-related alterations in brain metabolite levels in healthy adult women using 1H MRS at 3T: Effects of exposure to early-life stress1Center for Stroke Researech Berlin (CSB), Charite Universitätsmedizin Berlin, Berlin, Germany, 2Institute of Medical Psychology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, 3Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States, 4Development, Health, and Disease Research Program, University of California, Irvine, Orange, CA, United States, 5Neurocure Cluster of Excellence, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany, 6Department of Neurology with Experimental Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Synopsis
Keywords: Spectroscopy, Neuro, early-life stress, adverse childhood experiences, age-related, brain metabolites
Motivation: Adversity experienced during early life termed early-life stress (ELS) might increase the risk for neuroinflammation and neurodegenerative disorders in the adult human brain. An enhanced understanding of these relationships will aid in diagnosis and intervention.
Goal(s): Our goal was to investigate whether ELS is associated with changes in brain metabolism by using 1H MR spectroscopy.
Approach: The interaction between metabolite concentrations obtained from MRS, acquired in adult women, age, and scores of ELS was modeled using non-linear statistics.
Results: Higher concentrations with increasing age in individuals exposed to ELS were found for specific metabolites suggesting long-term effects of ELS on the human brain.
Impact: Understanding the role of early-life stress (ELS) in driving neuroinflammatory processes and identification of specific biomarkers to assess the risk for accelerated cognitive decline and neurodegenerative disorders in individuals exposed to ELS will aid in early identification and targeted interventions.
Introduction
Experience shapes the developing brain, and adversity during sensitive periods of developmental plasticity is termed early-life stress (ELS). Results from preclinical and clinical studies suggest that ELS causes major alterations in neural circuits implicated in emotion regulation and stress adaptation1. ELS induces sensitization of endocrine and autonomic stress responses and hinders the ability to fine-regulate these responses due to glucocorticoid receptor (GR) resistance. Via activation of GR in the hippocampus (HC)2, ELS impairs the structure and function of this brain region that undergoes significant development in early life. A second region of interest is the posterior cingulate gyrus (PCG), a highly connected and metabolically active brain area3 that is also indicated in cognitive impairment4. In addition, it is a central node of the default mode network (DMN)5 known to be affected by stress6. Despite overwhelming and mechanistically informed evidence for an impact of ELS on brain structure and immune activation, it is not known whether systemic inflammation after ELS translates to the adult brain in humans, thereby facilitating neuroinflammatory processes with impact on cognitive decline and age-related brain disease. Thus, the aim of this study was to elucidate whether ELS is associated with changes in brain metabolism in adult women as measured using 1H MR spectrosocopy (MRS).Methods
Seventy-nine adult healthy women (aged 30 – 60 yrs), including subjects with and without exposure to ELS, participated in structured interviews and questionnaires and MRS acquisitions.ELS Assessment: Exposure to ELS (occurring prior to the onset of menstruation) was ascertained using the Childhood Trauma Questionnaire (CTQ)7 and the Comprehensive Trauma Interview (CTI)8. Five dimensions of childhood maltreatment were assessed by using cut-off values for moderate or severe exposure provided by the CTQ manual. Other stressors were included by counting additional items in the CTI that correspond to Adverse Childhood Experiences (ACE)9. A comprehensive ACE-score ranging from 0 to 11 was created by combining the five childhood maltreatment categories with six stressors.
MRS: Scans were performed on a 3T PrismaFit system (Siemens Healthineers, Erlangen, Germany) using a 64 channel radiofrequency (RF) coil. For 1H MRS, localized RF calibration was performed, and first- and second-order shims were adjusted using FAST(EST)MAP10. Voxel placement was facilitated using high-resolution T1-weighted MPRAGE images. Single volume spectra were acquired from the HC and PCG using the semi-LASER technique11 (TR/TE = 3000/23 ms, spectral width = 2000 Hz, VOIHC = 10x12x35 mm3, number of averages (NA)HC = 256, VOIPCG = 20x20x20 mm3, NAPCG = 128). The FID-A toolkit12 was used for pre-processing of MRS data. Resulting spectra were analyzed using LCModel13 with a simulated basis set.
Statistics: Statistical analyses were conducted using Generalized Additive Models (GAMs)14. GAMs were fitted to the data using tensor product smoothing to model the interaction between age and ACE scores – both as continuous predictors – using the Restricted Maximum Likelihood method. All statistical analyses were run in R Project for Statistical Computing (R Core Team) with the significance level set at p<0.05.
Results
Shimming resulted in water linewidths of 8.0 ± 0.8 Hz (HC) and 6.0 ± 0.4 Hz (PCG), respectively. Cases with poor shim in the HC (LWH2O > 10 Hz) were excluded, such that NHC = 71. Analysis of high-quality spectra (Fig. 1) allowed quantification of neurochemical profiles in both regions including several metabolites (Fig. 2). Using GAMs, significant effects were found for myo-inositol (Ins) (p < 0.001), taurine (Tau) (p = 0.007), and glutamine (Gln) (p < 0.001), in the PCG (Fig. 3) indicating higher concentrations with increasing age in individuals exposed to ELS. No significant effects were observed for metabolites in the HC.Discussion
This study investigated whether neurochemical correlates of ELS (assessed by comprehensive ACE-scores) can be identified in the adult human female brain. Metabolite concentrations were successfully modelled by the interaction between age and ACE scores for Ins, Tau, and Gln in the PCG. Note that particularly with increasing age, the impact of ELS on metabolite levels become apparent, suggesting long-term effects of ELS on the human brain. Tau is reported to modulate the action of neurotransmitters15, and Gln is involved in neurotransmitter metabolism via the Gln-Glu cycle16. Hence, results for Tau and Gln might hint at a dysfunctional regulation of excitatory neuron-gliatransmission17. Finally, the finding of elevated Ins, considered a marker of neuroinflammation18, may confirm that neuroinflammatory processes are facilitated by ELS. Examining correlations with other markers of neuroinflammation will be crucial for a more comprehensive understanding of these observations.Conclusion
Exposure to ELS can be linked to age-related alterations in specific brain metabolite concentrations in healthy adult women.Acknowledgements
Funded by DFG EXC 2049 BrainLab Grant to Professor Christine Heim and Professor Matthias Endres.References
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