Advances in Magnetic Resonance Imaging (MRI) have made it possible to noninvasively and in vivo quantify metals, such as iron, that accumulate in the brain, notably by using susceptibility weighted imaging (SWI). In the brain, iron is found in two forms: heme iron, found in the blood, and intra-cellular nonheme iron, most of which is stored in ferritin protein. Nonheme iron is a fundamental element that contributes to cellular metabolism. However, an increase in free nonheme iron accumulation (out of ferritin, due to deterioration of transport and storage mechanisms) is highly toxic, inducing oxidative stress, cellular degradation, and cell death. Excessive concentration of iron in selective regions of the brain (basal ganglia, hippocampus) has been found in disorders such as Parkinson’s disease and Alzheimer’s disease and also in non-pathological aging. In addition, some studies have shown associations between iron concentration and cognitive performance. However, no study has yet evaluated the impact of brain iron concentration on brain activity that is related to cognitive or psychomotor processes as measured by functional MRI.
The aim of the IRON protocol is to seek associations between age-related iron concentration and brain activity during the performance of psychomotor and cognitive tasks. IRON will include 40 healthy individuals aged 30–80 years who will undergo MRI with a 3 Tesla GE scanner (including SWI and functional MRI) and offline psychomotor and cognitive testing. This protocol will be followed by a large-scale longitudinal study that will include 250 individuals. This second protocol will add MR-Spectroscopy to quantify metabolites in the brain and their impact on structure, function, and cognitive decline over time. Moreover, blood sampling will allow us to measure iron components in the blood and perform genetic studies after DNA extraction (for example by investigating the effects of variations in iron genes on several neural and cognitive outcomes). These studies will be extended to neurodegenerative disorders.
The quantification of brain iron and metabolites adds specificity to pathological mechanisms associated with brain aging and may explain motor and cognitive decline. Changes in local iron and metabolite concentrations in the brain may constitute biological markers for age-related cognitive decline and, possibly, development of neurodegenerative diseases.
The principal investigator for this project is Grégoria Kalpouzos. ARC collaborators in this project are Jonas Persson, Lars Bäckman, and Alireza Salami. External collaborators include Rouslan Sitnikov from the Department of Clinical Neuroscience, Karolinska Institute; Naftali Raz and Ana Daugherty from the Institute of Gerontology, Wayne State University, Detroit, United States; and Kenneth Hugdahl, Department of Biological and Medical Psychology, Bergen University, Norway.