Iron Status at Perimenopause: Effects on Brain and Behavior

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Project summary/abstract From the onset of menarche, through the child-bearing years, a substantial number of women worldwide are challenged by iron deficiency (ID) or iron deficiency anemia (IDA). The negative effects of ID include deficits in cognitive and physical performance. At and following menopause, however, the nature of the relationship between iron status and both cognitive performance and brain health is much more ambiguous, and the literature on these relationships is quite sparse, in spite of evidence suggesting that brain iron accumulation may play a role in neural degeneration and cognitive decline. One intriguing potential regularity in the literature is an inverse relationship between systemic levels of ferritin and performance on a range of memory tasks in peri- and post-menopausal women. This suggests that amenorrhea may produce differential changes in brain iron for women who are ID or IDA at or prior to menopause relative to those who are not. There are at least two competing possibilities. First, when blood loss stops, brain iron levels may accelerate in a manner inversely proportional to systemic iron levels. For ID women, this may reverse any deficits that may be due to ID, but accelerate the negative effects of iron deposits (including oxidative stress) in specific brain regions, including those critical to attention and memory. Second, the rate of brain iron accumulation may have no relationship to iron status at menopause. For women who are ID, this would mean that brain iron levels, although increasing over time (and thus, eventually, reversing any ID-related deficits) would remain lower than those of women who are iron sufficient (IS), possibly conferring a protective benefit with respect to the adverse effects of accumulating iron on brain tissue and function. The ability to address these possibilities depends on the feasibility of measuring relationships among levels of iron in the blood, levels of iron in brain in regions known to be involved in specific aspects of cognition, brain dynamics during cognitive work and at rest, and behavioral measures of specific aspects of cognition. This project will be, to our knowledge, the first to assess the feasibility of assessing all of these relationships. A set of non-anemic pre-, peri-, and post-menopausal women, half of whom have low levels of blood iron and half of whom are sufficient, will provide structural brain scans for region-specific estimates of brain iron. They will be tested on behavioral measures of cognitive performance that selectively engage those regions while having brain activity measured using electroencephelography (EEG), and will also have EEG recorded during two periods of rest. All of this will allow for the first known quantitative characterization of the relationships among blood and brain iron levels, brain dynamics (both at work and at rest), and behavior, all relative to the onset of menopause. This cross-sectional characterization will provide the data that are critically needed for an efficient longitudinal examination of these questions, and will represent a unique contribution to a now-sparse literature on the relationship between iron and brain health and cognition in women in later life.