Effect of age and the APOE gene on metabolite concentrations in the posterior cingulate cortex

Sana Suri, Uzay Emir, Charlotte J Stagg, Jamie Near, Ralf Mekle, Florian Schubert, Enikő Zsoldos, Abda Mahmood, Archana Singh-Manoux, Mika Kivimäki, Klaus P Ebmeier, Clare E Mackay, Nicola Filippini, Sana Suri, Uzay Emir, Charlotte J Stagg, Jamie Near, Ralf Mekle, Florian Schubert, Enikő Zsoldos, Abda Mahmood, Archana Singh-Manoux, Mika Kivimäki, Klaus P Ebmeier, Clare E Mackay, Nicola Filippini

Abstract

Proton magnetic resonance spectroscopy (1H-MRS) has provided valuable information about the neurochemical profile of Alzheimer's disease (AD). However, its clinical utility has been limited in part by the lack of consistent information on how metabolite concentrations vary in the normal aging brain and in carriers of apolipoprotein E (APOE) ε4, an established risk gene for AD. We quantified metabolites within an 8cm3 voxel within the posterior cingulate cortex (PCC)/precuneus in 30 younger (20-40 years) and 151 cognitively healthy older individuals (60-85 years). All 1H-MRS scans were performed at 3T using the short-echo SPECIAL sequence and analyzed with LCModel. The effect of APOE was assessed in a sub-set of 130 volunteers. Older participants had significantly higher myo-inositol and creatine, and significantly lower glutathione and glutamate than younger participants. There was no significant effect of APOE or an interaction between APOE and age on the metabolite profile. Our data suggest that creatine, a commonly used reference metabolite in 1H-MRS studies, does not remain stable across adulthood within this region and therefore may not be a suitable reference in studies involving a broad age-range. Increases in creatine and myo-inositol may reflect age-related glial proliferation; decreases in glutamate and glutathione suggest a decline in synaptic and antioxidant efficiency. Our findings inform longitudinal clinical studies by characterizing age-related metabolite changes in a non-clinical sample.

Keywords: APOE gene; Aging; Magnetic resonance spectroscopy; Metabolites; Posterior cingulate cortex; Precuneus.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
(A) Placement of the 8 cm3 1H-MRS voxel in the PCC/precuneus on a midline T1-weighted image. (B-C) Example 1H-MRS spectra showing the LCModel fit (Version 6.3-1B) for a participant from the (B) younger and (C) older age group. The lower black curve is the baseline. The data is plotted as a thin black spectrum and the LCModel fit to the data is the thick red spectrum. The top panel contains the residuals, which are fairly scattered about zero, indicating a good fit of the model to the data. Abbreviations: A: anterior, P: posterior, S: superior, I: inferior.
Fig. 2
Fig. 2
The effect of age on metabolites. Graphs show significant reductions in glutathione and glutamate, and increases in myo-inositol and creatine in the older group. Spectral line width, sex, voxel GM and CSF content were included as covariates. Metabolites are expressed as normalised concentrations. Bars represent means±SD. *p

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