Genetic predisposition for inflammation exacerbates effects of striatal iron content on cognitive switching ability in healthy aging

Abstract

Non-heme iron homeostasis interacts with inflammation bidirectionally, and both contribute to age-related decline in brain structure and function via oxidative stress. Thus, individuals with genetic predisposition for inflammation may be at greater risk for brain iron accumulation during aging and more vulnerable to cognitive decline. We examine this hypothesis in a lifespan sample of healthy adults (N = 183, age 20-94 years) who underwent R2*-weighted magnetic resonance imaging to estimate regional iron content and genotyping of interleukin-1beta (IL-1β), a pro-inflammatory cytokine for which the T allelle of the single nucleotide polymorphism increases risk for chronic neuroinflammation. Older age was associated with greater striatal iron content that in turn accounted for poorer cognitive switching performance. Heterozygote IL-1β T-carriers demonstrated poorer switching performance in relation to striatal iron content as compared to IL-1β C/C counterparts, despite the two groups being of similar age. With increasing genetic inflammation risk, homozygote IL-1β T/T carriers had lesser age-related variance in striatal iron content as compared to the other groups but showed a similar association of greater striatal iron content predicting poorer cognitive switching. Non-heme iron and inflammation, although necessary for normal neuronal function, both promote oxidative stress that when accumulated in excess, drives a complex mechanism of neural and cognitive decline in aging.

Keywords: Aging; Inflammation; Iron; R2* imaging; Structural equation modeling; Task switching.

Figure 1.

Example R2*-weighted imaging for the estimation of striatal iron content. R2*- weighted images were created from a multi-echo susceptibility weighted imaging sequence collected in the axial-plane with 0.5 × 0.5 × 2 mm³ voxels. (A) The first echo magnitude image served as an anatomical reference. (B) Estimates of iron content were taken from the R2*- weighted map via circular masks manually placed in each hemisphere of the caudate nucleus (red) and putamen (yellow) on three contiguous slices. On R2*-weighted images, brighter intensity values correspond to proportionally greater iron content. (C) The R2*-weighted image with regional masks is shown with x4 magnification.

Figure 2.

A depiction of the structural equation model that estimated age-related differences in cognitive switching ability, mediated by striatal iron content, in the entire sample. Standardized coefficients are reported with significance indicated, * p < 0.05, and unstandardized coefficients are reported in italics in parentheses (unstandardized). Parameters for measurement model specification are illustrated; factor loadings for cognitive switching ability that are labeled as negative were specified in order for higher values to indicate better ability. Older age was associated with greater striatal iron content that, in turn, predicted poorer cognitive switching ability.

Figure 3.

Average effects of age and striatal iron content as estimated in the total sample. Regression lines (solid, bold line) are shown with 95% confidence intervals (solid line) and predictive intervals (broken line). (A) Older age was associated with greater latent striatal iron content: b = 0.21 (standardized = 0.73), p < 0.001. (B) Greater latent striatal iron content, in turn, predicted poorer cognitive switching ability: b = −0.26 (standardized = −0.72), p < 0.001.

Figure 4.

A depiction of the grouped structural equation model that estimated age-related differences in cognitive switching ability, mediated by striatal iron content, in each IL-1β genetic group. Unstandardized coefficients are reported and significant effects are indicated with a solid line (*p < 0.05), and non-significant effects with a broken line. Carriage of the IL-1β T allele was associated with greater consequence of striatal iron content on cognitive switching ability as compared to IL-1β C-homozygote counterparts.

Figure 5.

IL-1β genetic group differences in the magnitude of the effects of age and striatal iron content. (A) IL-1β T/T carriers demonstrated lesser age-related differences in striatal iron content as compared to the other groups. (B) IL-1β C/T carriers demonstrated poorer cognitive switching ability in relation to striatal iron content than IL-1β C/C carriers.