Associations between sex, systemic iron and inflammatory status and subcortical brain iron

Key Points Differences in subcortical brain iron levels were observed between males and females Females exhibited more associations between brain iron and systemic markers for iron than males. Males exhibited more associations between brain iron and systemic markers for inflammation than females. Background Brain iron is increased in several neurodegenerative diseases, with studies demonstrating relationships between increased subcortical iron and disease progression. However, the causes of increased brain iron remain unclear. This study investigates relationships between subcortical iron and systemic iron and inflammatory status to improve our understanding of brain iron accumulation. Methods Brain MRI scans and blood plasma samples were collected from cognitively healthy females (n=176, mean age = 61.4 ± 4.5 y, age range = 28 - 72 y) andmales (n=152, mean age = 62.0 ± 5.1 y, age range = 32 - 74 y). Quantitative susceptibility mapping was used to quantify regional brain iron. To assess systemic iron, haematocrit, plasma ferritin and plasma soluble transferrin receptor (sTfR) were measured and total body iron index (TBI) was calculated. To assess systemic inflammation, C-reactive protein (CRP), Neutrophil/Lymphocyte ratio (NLR), plasma macrophage colony stimulating factor 1 (MCSF), plasma interleukin 6 (IL6) and plasma interleukin 1β (IL1β) were measured. Results Females exhibited associations between TBI and iron levels in the left and right caudate and right pallidum. Females also exhibited associations between haematocrit and iron levels in the right pallidum and left putamen. However, in males, the only association between brain iron and iron status was a positive correlation between iron in the right caudate and ferritin. In males, positive associations were observed between CRP levels and iron in the right thalamus and between IL6 levels and iron in the right amygdala and right pallidum. Males also exhibited a negative association between IL6 levels and iron in the left caudate. Positive associations between iron in the left thalamus and NLR were observed in both sexes. Conclusions This study demonstrates differential relationships between systemic iron and inflammation markers and brain iron in females and males. These results suggest differing iron regulation mechanisms in older age between sexes which could lead towards an understanding of the differences in neurodegenerative disease prevalence in males and females.