Influences of brain iron and glutamate on changes in brain activity during working memory in aging
Poster No:
1143
Submission Type:
Abstract Submission
Authors:
Jonatan Gustavsson1, Farshad Falahati2, Rouslan Sitnikov3, Amirhossein Manzouri4, Goran Papenberg1, Alireza Salami5, Jonas Persson6, Grégoria Kalpouzos7
Institutions:
1Aging Research Center, Karolinska Institutet, Stockholm, Stockholm, 2Aging Research Center, Karolinska Institutet, Stockholm, Sweden, 3MRI Research Center, Karolinska University Hospital, Stockholm, Stockholm, 4Department of Psychology, Stockholm University, Stockholm, Stockholm, 5Karolinska Institutet & Umeå University, Stockholm, Stockholm, 6Karolinska Institutet, Stockholm, Sweden, 7Karolinska Institutet, Stockholm, Stockholm
First Author:
Co-Author(s):
Introduction:
Iron is vital for several neurobiological mechanisms, such as neurotransmitters' synthesis. However, brain iron overload, associated with age-related iron dyshomeostasis, is detrimental as it leads to oxidative stress and neuroinflammation1. This likely contributes to alterations in neural-activity (as measured with blood oxygen level-dependent magnetic resonance imaging (BOLD MRI)) and cognitive deficits, including working memory2,3. Astrocytes are responsible for transporting glutamate, a neurotransmitter with antioxidant properties protecting the brain tissue from inflammatory insults4. They are also vulnerable to heavy metal toxicity, which can lead to BOLD alteration since astrocytes are involved in neurovascular coupling5,6. A healthy glutaminergic system may attenuate iron-mediated damage such as BOLD deficits. However, cross-sectional and longitudinal studies on the iron-glutamate relationship are lacking, with only one study linking more blood iron to less glutamate7.
Methods:
Using data from the 3-year longitudinal IronAge project (baseline n = 208; 20–79 years, follow-up n = 135), we aimed to investigate (1) the relationship between brain iron and glutamate as a function of age, (2) if brain iron content is linked to longitudinal changes of brain activity in normal aging, and (3) whether glutamate mediates the relationship between brain iron and brain activity. Participants underwent MRI (3.0T GE scanner) to assess brain iron, glutamate, and brain activity during an N-back working-memory task. Iron content was assessed using quantitative susceptibility mapping and glutamate concentration was measured using 1H MR spectroscopy in striatum and dorsolateral prefrontal cortex (DLPFC). Functional MRI data were processed with fmriprep and analyzed in SPM12 software. Working memory performance was calculated as d' (d-prime).
Results:
Firstly, whereas there were no significant associations between iron and glutamate in the whole sample (striatum: r = -0.04, p = 0.7; DLPFC: r = 0.006, p = 0.9), we found differential relationships in DLPFC when stratifying by age group (Figure 1): In younger adults (20-39 years old), higher iron was related to higher glutamate at trend level, but in older adults (60-79) higher iron was associated with lower glutamate (younger: r = 0.34, p = 0.06; middle-aged: r = 0.014, p = 0.4; older: r = -0.33, p = 0.03). Secondly, difference of activation during 2- and 3-back (contrasted with 1-back) between the 2 timepoints showed decreased activation in right DLPFC (p < 0.001) over time at a group level (Figure 2). A multiple regression model revealed no association between activation and baseline iron in DLPFC (β = -0.097, p = 0.3). However, stratifying by age groups showed that decreased activation was associated with more baseline iron in DLPFC among younger adults only (younger: β = -0.48, p = 0.01; middle-aged: β = 0.16, p = 0.3; older: β = 0.06, p = 0.7). Further, there were no associations with glutamate at baseline (ps > 0.3). Thirdly, glutamate did not improve the fit of the model (R2 change = 0.01), nor did it attenuate the association between iron and activation. Finally, neither baseline iron nor glutamate were related to working memory performance in the whole group (ps > 0.3) nor within age groups (ps > 0.2).
·Figure 1
·Figure 2
Conclusions:
These findings indicate an association between iron and glutamate in the human brain that is modulated by age. The opposite patterns observed between younger and older adults may reflect the progress of astrocytic dysfunction; in young age iron is still in homeostasis, whereas in old age iron dyshomeostasis disrupts the glutaminergic system. Further, our results indicate that glutamate does not play a role in the relationship between iron content and decreased DLPFC activation during working memory performance.
Learning and Memory:
Working Memory
Lifespan Development:
Aging 1
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Cortical Anatomy and Brain Mapping 2
Transmitter Systems
Novel Imaging Acquisition Methods:
BOLD fMRI
Keywords:
Aging
Cognition
Cortex
FUNCTIONAL MRI
Glutamate
Memory
MRI
Neurotransmitter
Other - Iron
1|2Indicates the priority used for review
Provide references using author date format
2 Kalpouzos, G., Garzón, B., Sitnikov, R., Heiland, C., Salami, A., Persson, J., & Bäckman, L. (2017). Higher Striatal Iron Concentration is Linked to Frontostriatal Underactivation and Poorer Memory in Normal Aging. Cerebral Cortex, 27(6), 3427–3436. https://doi.org/10.1093/cercor/bhx045
3 Daugherty, A. M., Haacke, E. M., & Raz, N. (2015). Striatal iron content predicts its shrinkage and changes in verbal working memory after two years in healthy adults. Journal of Neuroscience, 35(17), 6731–6743. https://doi.org/10.1523/JNEUROSCI.4717-14.2015
4 Li, B., Xia, M., Zorec, R., Parpura, V., & Verkhratsky, A. (2021). Astrocytes in heavy metal neurotoxicity and neurodegeneration. Brain Research, 1752(77), 147234. https://doi.org/10.1016/j.brainres.2020.147234
5 Dringen, R., Bishop, G. M., Koeppe, M., Dang, T. N., & Robinson, S. R. (2007). The Pivotal Role of Astrocytes in the Metabolism of Iron in the Brain. Neurochemical Research, 32(11), 1884–1890. https://doi.org/10.1007/s11064-007-9375-0
6 Koehler, R. C., Roman, R. J., & Harder, D. R. (2009). Astrocytes and the regulation of cerebral blood flow. Trends in Neurosciences, 32(3), 160–169. https://doi.org/10.1016/j.tins.2008.11.005
7 Burger, A, Kotze, MJ, Stein, DJ, Janse van Rensburg, S, Howells, FM. The relationship between measurement of in vivo brain glutamate and markers of iron metabolism: A proton magnetic resonance spectroscopy study in healthy adults. Eur J Neurosci. 2020; 51: 984–990. https://doi.org/10.1111/ejn.14583