Brain Iron Mediates the Relationship Between Cognition and Neighborhood Socioeconomic Status in Youth

Non-heme brain iron is a critical metabolic cofactor essential for healthy brain development.1 Iron deficiency is the most common nutritional disorder in the world, with greater prevalence of non-heme iron deficiency among individuals of lower socioeconomic status (SES). However, it remains unknown how brain iron accumulation during development may impact cognition. Brain iron can be measured in vivo using R2* weighted magnetic resonance imaging (MRI); prior work has established that higher R2* is associated with higher iron content.2,3 We hypothesized that more iron in the basal ganglia (BG) regions of the caudate, putamen, and pallidum would be associated with improved cognitive performance and potentially mediate the known relationship between neighborhood-level socioeconomic status (SES) and cognition.4


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Iron deficiency is the most common nutritional disorder in the world, with greater prevalence of 50 non-heme iron deficiency among individuals of lower socioeconomic status (SES). However, it 51 remains unknown how brain iron accumulation during development may impact cognition. Brain 52 iron can be measured in vivo using R2* weighted magnetic resonance imaging (MRI); prior work 53 has established that higher R2* is associated with higher iron content. 2,3 We hypothesized that 54 more iron in the basal ganglia (BG) regions of the caudate, putamen, and pallidum would be 55 associated with improved cognitive performance and potentially mediate the known relationship 56 between neighborhood-level socioeconomic status (SES) and cognition. 4 57 58 59

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We quantified BG iron in a large sample of youth ages 8-23 imaged as part of the Philadelphia 62 Neurodevelopmental Cohort (PNC), a community-based study of brain development. 5 In total, 63 we considered 1,147 youth (mean age 14.90, SD = 3.61; 524 males and 623 females), after 64 excluding those with missing data, poor quality imaging, or medical problems that could impact 65 brain function. All participants completed the Penn Computerized Neurocognitive Battery (CNB); 66 overall accuracy was summarized from the CNB using factor analysis. 6 Socioeconomic status 67 was quantified on the neighborhood level as in previous work from the PNC. 4

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All participants completed both structural imaging and a multi-echo sequence that 69 allowed quantification of R2*. BG structures were delineated for each subject using an 70 advanced multi-atlas labeling procedure. Mean R2* signal within each bilateral BG region was 71 modeled using generalized additive models (GAM) with penalized splines to capture both linear 72 and nonlinear age effects. We investigated main effects of age, sex, race, and cognition at each 73 region while correcting for multiple comparisons using the False Discovery Rate (q<0.05); 74 interactions were evaluated but found to be non-significant. Finally, we tested whether BG iron

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As expected from prior reports, R2* increased in the BG throughout youth (Figure 1; all regions 85 p fdr <0.001); no sex differences or age by sex interactions were present. Across all ages, lower 86 R2* levels in the caudate (p fdr <0.02) was associated with diminished cognitive performance.

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Lower neighborhood SES was associated with both diminished cognition (p<0.001), as well as 88 lower R2* in the caudate (p fdr =0.02). Even when controlling for maternal education, SES 89 remained significantly associated with caudate R2* (p=0.03). Critically, the relationship between 90 cognition and SES was significantly mediated by caudate R2* (Figure 2; p=0.007). Including 91 data quality as a covariate did not impact results.

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Leveraging a large sample of youth imaged as a part of the PNC, we replicate prior results 97 documenting that brain iron indexed by R2* accumulates with age in the basal ganglia in 98 youth. 1,3 Additionally, we provide novel evidence that lower levels of caudate iron is associated with diminished cognitive performance during adolescence. Importantly, lower neighborhood-100 level SES is also associated with caudate brain iron, and brain iron significantly mediated the 101 relationship between cognition and SES. While speculative, it is possible that these effects are 102 due to neighborhood-level differences in nutrition and the availability of iron-rich foods. Taken 103 together, these results suggest that brain iron is important for facilitating cognitive development 104 in youth, and may provide a mechanism by which public health interventions focused on 105 improving nutrition in low SES neighborhoods might aid cognitive development.