Determinants of age-related brain iron accumulation and links to neurocognitive functions

Iron is crucial for development and normal functioning of the brain. With increasing age, it accumulates in the cells and can cause irreparable damage, affecting both the structure and function of the brain. Despite these findings, the factors which influence iron accumulates and the longitudinal effects of iron are still poorly understood. This doctoral thesis aimed to explore what influences brain iron accumulation in normal aging, and how this accumulation impacts molecular, and functional properties of the brain, and working-memory.

Study I investigated if iron accumulation in striatum and DLPFC affected working memory change in normal aging, and if this accumulation and relationship to performance varied based on availability of dopamine, specified by COMT genotype status. We found that iron accumulated in both striatum and DLPFC. Greater iron accumulation in DLPFC was related to more deleterious change in working-memory performance. In addition, iron accumulation was amplified in older adults with presumably lowest levels of dopamine. These individuals were also driving the link between changes in iron and working-memory performance.

Study II investigated if iron was linked to dopamine receptor availability and whether this association affected working memory. The study revealed that more iron was related to lower receptor availability in DLPFC and that this, coupled together with older age, contributed to reduced brain activity during a working-memory task. Additionally, the reduction in brain activity was in turn related to poorer task performance.

Study III assessed (1) if brain iron content and accumulation were related to longitudinal changes in in brain activity during working-memory performance in normal aging, (2) potential association with glutamate, and (3) whether glutamate mitigated iron-brain activity relationship. In this study, we found that younger adults with initial elevated iron down-regulated more brain activity over a 3-year period, while performing the task. The results also showed a potential age-dependent relationship between iron and glutamate, such that younger adults with elevated iron content had more glutamate in DLPFC.

Study IV explored biological and lifestyle factors that might influence iron accumulation in normal aging. Here, blood iron markers, physical activity, diet, and cardiovascular health significantly influenced brain iron content and accumulation. Furthermore, the associations between these factors and brain iron were influenced by age, highlighting the complexity of these relationships.

Collectively, our studies show that age-related brain iron accumulation can be influenced by a number of factors, both modifiable and non-modifiable, such as lifestyle choices and genetic predisposition respectively. The potential to attenuate the accumulation of brain iron is essential, as we have also shown that iron can have deleterious effects on brain function and cognition older age. Finally, the links between iron and the dopaminergic system could partially explain age-related alterations, such as diminished receptor availability. Understanding the role of neurotransmitters on attenuating iron accumulation can pave the way for tailoring interventions in neurodegenerative disorders.

List of scientific papers

I. Gustavsson, J*., Papenberg, G*., Falahati, F., Laukka, E. J., & Kalpouzos, G. (2022). Contributions of the Catechol-O-Methyltransferase Val158Met Polymorphism to Changes in Brain Iron Across Adulthood and Their Relationships to Working Memory. Frontiers in Human Neuroscience. 16. *Authors contributed equally to this work as first authors.
https://doi.org/10.3389/fnhum.2022.838228

II. Gustavsson, J., Johansson, J., Falahati, F., Andersson, M., Papenberg, G., Avelar-Pereira, B., Bäckman, L., Kalpouzos, G., & Salami, A. (2023). The irondopamine D1 coupling modulates neural signatures of working memory across adulthood. NeuroImage. 2023, 279:12323.
https://doi.org/10.1016/j.neuroimage.2023.120323

III. Gustavsson, J., Falahati, F., Sitnikov, R., Manzouri, A., Papenberg, G., Salami, A., Persson, J., Kalpouzos, G. Influences of brain iron and glutamate on changes in brain activity during working memory in aging. [Manuscript]

IV. Gustavsson, J., Ištvánfyová, Z., Papenberg, G., Falahati, F., Laukka, E. J., Lehtisalo, J., Mangialasche, F., Kalpouzos, G. Lifestyle, biological and genetic determinants of brain iron accumulation across adulthood. [Submitted]