The iron-dopamine D1 coupling modulates neural signatures of working memory across adult lifespan
Jonatan Gustavsson,
Jarkko Johansson,
Farshad Falahati,
Micael Andersson,
Goran Papenberg,
Bárbara Avelar-Pereira,
Lars Bäckman,
Grégoria Kalpouzos,
Alireza Salami
Affiliations
Jonatan Gustavsson
Aging Research Center, Karolinska Institutet and Stockholm University, Sweden; Corresponding author.
Jarkko Johansson
Faculty of Medicine, Department of Radiation Sciences, Umeå University, Sweden; Umeå Center for Functional Brain Imaging, Umeå University, Umeå, Sweden
Farshad Falahati
Aging Research Center, Karolinska Institutet and Stockholm University, Sweden
Micael Andersson
Umeå Center for Functional Brain Imaging, Umeå University, Umeå, Sweden; Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
Goran Papenberg
Aging Research Center, Karolinska Institutet and Stockholm University, Sweden
Bárbara Avelar-Pereira
Aging Research Center, Karolinska Institutet and Stockholm University, Sweden; Department of Psychiatry and Behavioural Sciences, School of Medicine, Stanford University, Stanford, California 94304, USA
Lars Bäckman
Aging Research Center, Karolinska Institutet and Stockholm University, Sweden
Grégoria Kalpouzos
Aging Research Center, Karolinska Institutet and Stockholm University, Sweden
Alireza Salami
Aging Research Center, Karolinska Institutet and Stockholm University, Sweden; Umeå Center for Functional Brain Imaging, Umeå University, Umeå, Sweden; Department of Integrative Medical Biology, Umeå University, Umeå, Sweden; Wallenberg Center for Molecular Medicine, Umeå University, Sweden
Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention.
