Quantitative Susceptibility Mapping of Iron Accumulation in Neurocognitive Aging

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Iron concentration in deep gray matter (DGM) regions is associated with neurodegenerative disease, but DGM iron also increases with adult age, in the absence of disease. Previous studies have reported association between age-related DGM iron accumulation and decline in some aspects of neurocognitive function. However, previous studies have typically focused on a limited number of neurocognitive outcome measures, often biased towards motor functioning, and have relied on less than optimal MRI methods to estimate iron concentration, such as MRI relaxometry. Further, although decline in structural and functional brain connectivity appears to contribute to neurocognitive decline in healthy aging, the role of iron in this decline is not clear. In this project we test a model of the influence of age-related DGM iron accumulation on neurocognitive function, proposing that age-related DGM iron contributes to oxidative stress and consequently to a decline in network connectivity. The research will investigate the effects of DGM iron using Quantitative Susceptibility Mapping (QSM), a novel and validated technique that has several advantages over previous methods for estimating GM iron (e.g., relaxometry). This research comprises imaging and neurocognitive testing of 270 healthy, community-dwelling individuals, with 45 individuals in each of six age decades: 20s, 30s, 40s, 50s, 60s, and 70s. The participants in their 60s and 70s will be tested at two time points, approximately 3 years apart. Aim 1 will test the hypothesis that iron in the head of the caudate will have a greater mediating or moderating influence, on the relation between age and the neurocognitive measures, relative to other DGM regions, and that this influence will extend to measures of the efficiency of decision processes (drift rate). Aim 2 will test the hypothesis that age-related increase in DGM iron, particularly in the head of the caudate, influences structural and functional connectivity in a serial manner, with regionally specific associations among DGM iron, the white matter (WM) integrity of frontostriatal circuits, and the functional connectivity of associated resting-state networks (RSNs). Aim 3 will test the hypothesis that the age-related influences of DGM iron identified in Aims 1 and 2, in cross-sectional analyses, can be confirmed longitudinally, across a three-year interval. The project will consequently contribute to a more comprehensive theoretical model, than presently available, of the influence of DGM iron on the relation between age and neurocognitive performance. The findings will also be relevant to assessing the potential role of DGM iron as a biomarker of neurodegenerative disease.