Higher brain iron levels are associated with higher R2 in gray matter and higher white matter hyperintensities volume in community-based older adults

High brain iron levels in older adults have been associated with neuropathologies and cognitive decline. However, the independent association of iron levels with brain MRI characteristics above and beyond the effects of age-related neuropathologies is not yet known. This study investigated the association of R 2 relaxation rate and white matter hyperintensities (WMH) with brain iron concentration independently of neuropathologies, in community-based older adults. Ex vivo MRI, comprehensive neuropathologic examination, and molecular quantification of brain iron concentration from inductively coupled plasma mass spectrometry were combined in 424 community-based older adults. Voxel-wise linear regression revealed that higher values in the composite brain iron concentration metric were associated with higher R 2 values in gray matter across the cerebrum independently of age-related neuropathologies and demographics, with the strongest association observed in the globus pallidus (β = 5.8 \\(\\frac{{sec}^{-1}}{{log}_{10}[\\text{I}\\text{r}\\text{o}\\text{n } \\upmu \\text{g}/\\text{g } \\text{t}\\text{i}\\text{s}\\text{s}\\text{u}\\text{e}]}\\) , 95% CI (2.7, 8.9)). Higher brain iron concentration was also associated with greater WMH burden in the cerebrum over all (β = 0.43 \\(\\frac{{log}_{10}\\left(\\frac{WMH \\: vol, {\\:mm}^{3}}{Hemisphere \\: vol, {\\:mm}^{3}}\\right)}{{log}_{10}[\\text{I}\\text{r}\\text{o}\\text{n } \\upmu \\text{g}/\\text{g } \\text{t}\\text{i}\\text{s}\\text{s}\\text{u}\\text{e}]}\\) , 95% CI (0.08, 0.77)), and particularly in the frontal (β = 0.50 \\(\\frac{{log}_{10}\\left(\\frac{WMH \\: vol, {\\:mm}^{3}}{Hemisphere \\: vol, {\\:mm}^{3}}\\right)}{{log}_{10}[\\text{I}\\text{r}\\text{o}\\text{n } \\upmu \\text{g}/\\text{g } \\text{t}\\text{i}\\text{s}\\text{s}\\text{u}\\text{e}]}\\) , 95% CI (0.14, 0.86)) and temporo-basal ganglia white matter (β = 0.40 \\(\\frac{{log}_{10}\\left(\\frac{WMH \\: vol, {\\:mm}^{3}}{Hemisphere \\: vol, {\\:mm}^{3}}\\right)}{{log}_{10}[\\text{I}\\text{r}\\text{o}\\text{n } \\upmu \\text{g}/\\text{g } \\text{t}\\text{i}\\text{s}\\text{s}\\text{u}\\text{e}]}\\) , 95% CI (0.05, 0.76)), independently of neuropathologies and demographics. No negative associations were observed between brain iron concentration and R 2 or WMH burden. Analysis at different brain iron levels showed that higher R 2 and WMH were detectable even at intermediate iron levels. These findings underline the importance of iron homeostasis and the deleterious effects associated with high iron levels in the brain. The fact that the observed abnormalities were independent of the effects of age-related neuropathologies suggests the presence of orthogonal pathophysiology linked to iron dysregulation.